Modulators of the Cystic Fibrosis Transmembrane Conductance Regulator Protein and Methods of Use

ABSTRACT

wherein A1, R1, R2, R3, R4, and n are as defined herein. The present invention relates to compounds and their use in the treatment of cystic fibrosis, methods for their production, pharmaceutical compositions comprising the same, and methods of treating cystic fibrosis by administering a compound of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/129,548, filed Sep. 12, 2018, which claims priority to U.S.Provisional Application No. 62/558,430, filed Sep. 14, 2017 and U.S.Provisional Application No. 62/608,846, filed Dec. 21, 2017, both ofwhich are incorporated herein by reference for all purposes.

BACKGROUND OF THE INVENTION Technical Field

The invention relates to substituted pyridine compounds that aremodulators of the Cystic Fibrosis Transmembrane Conductance Regulator(CFTR) protein, useful in treating diseases and conditions mediated andmodulated by CFTR. The invention also relates to compositions containingcompounds of the invention, processes for their preparation, and methodsof treatment using them.

Description of Related Technology

Cystic fibrosis (CF) is caused by a defect in genes which inducemutations in CFTR. Cystic fibrosis is the most common fatal geneticdisease in humans, and affects ˜0.04% of white individuals, for example,in the United States, about one in every 2,500 infants is affected, andup to 10 million people carry a single copy of the defective genewithout apparent ill effects; moreover subjects bearing a single copy ofthe gene exhibit increased resistance to cholera and to dehydrationresulting from diarrhea. This effect might explain the relatively highfrequency of the CF gene within the population.

In contrast, individuals with two copies of the CF associated genesuffer from the debilitating and fatal effects of CF, including chroniclung infections. In cystic fibrosis patients, mutations in endogenousrespiratory epithelial CFTR fails to confer chloride and bicarbonatepermeability to epithelial cells in lung and other tissues, thus leadingto reduced apical anion secretion and disruptions of the ion and fluidtransport. This decrease in anion transport causes an enhanced mucus andpathogenic agent accumulation in the lung triggering microbialinfections that ultimately cause death in CF patients. Beyondrespiratory disease, CF patients also suffer from gastrointestinalproblems and pancreatic insufficiency that result in death if leftuntreated. Furthermore, female subjects with cystic fibrosis suffer fromdecreased fertility, whilst males with cystic fibrosis are infertile.

In addition to cystic fibrosis, CFTR activity modulation may bebeneficial for other diseases not directly caused by mutations in CFTR,such as chronic obstructive pulmonary disease (COPD), dry eye disease,and Sjögren's syndrome.

There is a need for novel compounds capable of modulating CFTR. Inparticular, the present invention discloses compounds that may act asCFTR modulators for the treatment of cystic fibrosis. The presentinvention also provides methods for the preparation of these compounds,pharmaceutical compositions comprising these compounds and methods forthe treatment of cystic fibrosis by administering the compounds of theinvention.

SUMMARY

In one aspect the invention provides for compounds of Formula (I), andpharmaceutically acceptable salts thereof,

wherein

-   -   A¹ is selected from the group consisting of C₃-C₇ cycloalkyl,        C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl;    -   R¹ is selected from the group consisting of 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R¹        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are        substituted with two or more substituents independently selected        from the group consisting of R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷,        C(O)OR⁷, SO₂R7, C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NHR⁷,        N(R⁷)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R² is independently selected from the group consisting of R⁸,        OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN,        NO₂, F, Cl, Br and I;    -   n is 0 or 1;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br        and I; wherein the R³ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R⁹, OR⁹, SR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹,        C(O)NH₂, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂,        C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆        alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with        one or more substituents independently selected from the group        consisting of OR¹⁰, F, Cl, Br and I;    -   R⁷, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, C₃-C₇ cycloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I;        wherein each R⁷ 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        R¹¹, OR¹¹, SR¹¹, C(O)R¹¹, OC(O)R¹¹, C(O)OR¹¹, SO₂R¹¹, C(O)NH₂,        C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH,        OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁸, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;        wherein each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        C(O)OR², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and        I;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹³, OR³,        SR¹³, C(O)R³, OC(O)R¹³, C(O)OR¹³, SO₂R¹³, C(O)NH₂, C(O)NHR³,        C(O)N(R³)₂, NHC(O)R¹³, NHR¹³, N(R³)₂, NH₂, C(O)OH, OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and        4-12 membered heterocyclyl is optionally substituted with one or        more substituents independently selected from the group        consisting of R⁴, OR⁴, SR¹⁴, C(O)R⁴, OC(O)R¹⁴, C(O)OR¹⁴, SO₂R¹⁴,        C(O)NH₂, C(O)NHR⁴, C(O)N(R⁴)₂, NHC(O)R⁴, NHR¹⁴, N(R⁴)₂, NH₂,        C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I; R¹⁰, at each        occurrence, is independently C₁-C₄ alkyl;    -   R¹¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered        aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁        cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹        C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one        or more substituents independently selected from the group        consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I;        wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12        membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered        aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁        cycloalkenyl, and 5-6 membered heteroaryl;    -   R¹³, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹³, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl        is optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6        membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and    -   R¹⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered        heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   with the proviso that the compound is not        1-(3,4-dimethylphenyl)-N-(naphthalene-1-sulfonyl)cyclopentane-1-carboxamide.

These and other objects of the invention are described in the followingparagraphs. These objects should not be deemed to narrow the scope ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

Described herein are compounds of Formula (I),

wherein A¹, R¹, R², R³, R⁴, and n are defined above in the Summary andbelow in the Detailed Description. Further, compositions comprising suchcompounds and methods for treating conditions and disorders using suchcompounds and compositions are also included.

Compounds included herein may contain one or more variable(s) that occurmore than one time in any substituent or in the formulae herein.Definition of a variable on each occurrence is independent of itsdefinition at another occurrence. Further, combinations of substituentsare permissible only if such combinations result in stable compounds.Stable compounds are compounds which can be isolated from a reactionmixture.

Definitions

It is noted that, as used in this specification and the intended claims,the singular form “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference to“a compound” includes a single compound as well as one or more of thesame or different compounds; reference to “a pharmaceutically acceptablecarrier” means a single pharmaceutically acceptable carrier as well asone or more pharmaceutically acceptable carriers, and the like.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C₂-C₆ alkenyl” means analkenyl group containing 2-6 carbon atoms. Non-limiting examples ofC₂-C₆ alkenyl include buta-1,3-dienyl, ethenyl, 2-propenyl,2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

The term “C₁-C₆ alkoxy” as used herein, means a C₁-C₆ alkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom. Non-limiting examples of alkoxy include methoxy, ethoxy,propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.

The term “alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain radical. In some instances, the number of carbon atomsin an alkyl moiety is indicated by the prefix “C_(x)-C_(y)”, wherein xis the minimum and y is the maximum number of carbon atoms in thesubstituent. Thus, for example, “C₁-C₆ alkyl” means an alkyl substituentcontaining from 1 to 6 carbon atoms and “C₁-C₄ alkyl” means an alkylsubstituent containing from 1 to 4 carbon atoms, and “C₁-C₃ alkyl” meansan alkyl substituent containing from 1 to 3 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl,1-ethylpropyl, and 1,2,2-trimethylpropyl. The terms “alkyl,” “C₁-C₆alkyl,” “C₁-C₄ alkyl,” and “C₁-C₃ alkyl” used herein are unsubstituted,unless otherwise indicated.

The term “alkylene” or “alkylenyl” means a divalent radical derived froma straight or branched, saturated hydrocarbon chain, for example, of 1to 10 carbon atoms or of 1 to 6 carbon atoms (C₁-C₆ alkylenyl) or of 1to 4 carbon atoms or of 1 to 3 carbon atoms (C₁-C₃ alkylenyl) or of 2 to6 carbon atoms (C₂-C₆ alkylenyl). Examples of C₁-C₆ alkylenyl include,but are not limited to, —CH₂—, —CH₂CH₂—, —C(CH₃)₂—CH₂CH₂CH₂—,—C(CH₃)₂—CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “C₂-C₆ alkynyl” as used herein, means a straight or branchedchain hydrocarbon radical containing from 2 to 6 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of C₂-C₆ alkynyl include, but are not limited, to acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “C₃-C₁₁ cycloalkyl” as used herein, means a hydrocarbon ringradical containing 3-11 carbon atoms, zero heteroatoms, and zero doublebonds. The C₃-C₁₁ cycloalkyl group may be a single-ring (monocyclic) orhave two or more rings (polycyclic or bicyclic). Monocyclic cycloalkylgroups typically contain from 3 to 8 carbon ring atoms (C₃-C₈ monocycliccycloalkyl), and even more typically 3-7 carbon ring atoms (C₃-C₇monocyclic cycloalkyl). Examples of monocyclic cycloalkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl. Polycyclic cycloalkyl groups contain two or more rings, andbicyclic cycloalkyls contain two rings. In certain embodiments, thepolycyclic cycloalkyl groups contain 2 or 3 rings. The rings within thepolycyclic and the bicyclic cycloalkyl groups may be in a bridged,fused, or spiro orientation, or combinations thereof. In a spirocycliccycloalkyl, one atom is common to two different rings. Examples of aspirocyclic cycloalkyl include spiro[2.5]octanyl and spiro[4.5]decanyl.In a bridged cycloalkyl, the rings share at least two non-adjacentatoms. Examples of bridged cycloalkyls include, but are not limited tobicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl,bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.2]nonyl,bicyclo[3.3.1]nonyl, and bicyclo[4.2.1]nonyl, tricyclo[3.3.1.0³′7]nonyl(octahydro-2,5-methanopentalenyl or noradamantyl),tricyclo[3.3.1.1^(3,7)]decyl (adamantyl), andtricyclo[4.3.1.1^(3,8)]undecyl (homoadamantyl). In a fused ringcycloalkyl, the rings share one common bond. Examples of fused-ringcycloalkyl include, but not limited to, decalin (decahydronaphthyl),bicyclo[3.1.0]hexanyl, and bicyclo[2.2.0]octyl.

The term “C₃-C₇ cycloalkyl” as used herein, means a hydrocarbon ringradical containing 3-7 carbon atoms, zero heteroatoms, and zero doublebonds. The C₃-C₇ cycloalkyl group may be a single-ring (monocyclic) orhave two rings (bicyclic).

The term “C₄-C₁₁ cycloalkenyl” as used herein, means a non-aromatichydrocarbon ring radical containing 4-11 carbon atoms, zero heteroatoms,and one or more double bonds. The C₄-C₁₁ cycloalkenyl group may be asingle-ring (monocyclic) or have two or more rings (polycyclic orbicyclic). Examples of monocyclic cycloalkenyl include cyclobutenyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctenyl,and cyclooctadienyl. Examples of bicyclic cycloalkenyl includebicyclo[2.2.1]hept-2-enyl.

The term “C₄-C₈ monocyclic cycloalkenyl” as used herein, meanscyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl,cycloheptadienyl, cyclooctenyl, and cyclooctadienyl.

The term “C₄-C₇ monocyclic cycloalkenyl” as used herein, meanscyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, andcycloheptyl.

The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five or six hydrogen atoms arereplaced by halogen. The term “C₁-C₆ haloalkyl” means a C₁-C₆ alkylgroup, as defined herein, in which one, two, three, four, five, or sixhydrogen atoms are replaced by halogen. The term “C₁-C₃ haloalkyl” meansa C₁-C₃ alkyl group, as defined herein, in which one, two, three, four,or five hydrogen atoms are replaced by halogen. Representative examplesof haloalkyl include, but are not limited to, chloromethyl,2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl,trifluoromethyl, difluoromethyl, pentafluoroethyl,2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl.

The term “4-12 membered heterocyclyl” as used herein, means ahydrocarbon ring radical of 4-12 carbon ring atoms wherein at least onecarbon atom is replaced by a heteroatom(s) independently selected fromthe group consisting of O, N, and S. The 4-12 membered heterocycle ringmay be a single ring (monocyclic) or have two or more rings (bicyclic orpolycyclic). In certain embodiments, the monocyclic heterocycle is afour-, five-, six-, seven-, or eight-membered hydrocarbon ring whereinat least one carbon ring atom is replaced by a heteroatom(s)independently selected from the group consisting of O, N, and S. Incertain embodiments, the monocyclic heterocycle is a 4-7 memberedhydrocarbon ring wherein at least one carbon ring atom is replaced by aheteroatom(s). A four-membered monocyclic heterocycle contains zero orone double bond, and one heteroatom selected from the group consistingof O, N, and S. A five-membered monocyclic heterocycle contains zero orone double bond and one, two, or three heteroatoms selected from thegroup consisting of O, N, and S. Examples of five-membered monocyclicheterocycles include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3N; 1 S and 1 N; 1 S, and 2 N; 10 and 1 N; or 1 O and 2 N. Non limitingexamples of 5-membered monocyclic heterocyclic groups include1,3-dioxolanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl,imidazolidinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl,pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, thiazolinyl, andthiazolidinyl. A six-membered monocyclic heterocycle contains zero, one,or two double bonds and one, two, or three heteroatoms selected from thegroup consisting of O, N, and S. Examples of six-membered monocyclicheterocycles include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1S and 2 O; 1 O and 1 N; and 1 O and 2 N. Examples of six-memberedmonocyclic heterocycles include dihydropyranyl, 1,4-dioxanyl,1,3-dioxanyl, 1,4-dithianyl, hexahydropyrimidine, morpholinyl,1,4-dihydropyridinyl, piperazinyl, piperidinyl, tetrahydropyranyl,1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl,thioxanyl, and trithianyl. Seven- and eight-membered monocyclicheterocycles contains zero, one, two, or three double bonds and one,two, or three heteroatoms selected from the group consisting of O, N,and S. Examples of monocyclic heterocycles include, but are not limitedto, azetidinyl, azepanyl, aziridinyl, 1,4-diazepanyl, dihydropyranyl,1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxazepanyl, oxadiazolinyl,oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. Polycyclicheterocycle groups contain two or more rings, and bicyclic heterocyclescontain two rings. In certain embodiments, the polycyclic heterocyclegroups contain 2 or 3 rings. The rings within the polycyclic and thebicyclic heterocycle groups may be in a bridged, fused, or spiroorientation, or combinations thereof. In a spirocyclic heterocycle, oneatom is common to two different rings. Non limiting examples of thespirocyclic heterocycle include 6-oxaspiro[2.5]octanyl,2-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.5]octyl,2-azaspiro[3.5]nonyl, 2-azaspiro[3.4]octyl, 3-azaspiro[5.5]undecyl,5-azaspiro[3.4]octyl, 2-oxaspiro[3.3]heptyl,2-oxa-6-azaspiro[3.3]heptyl, 6-oxa-2-azaspiro[3.4]octyl,6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decyl,1-oxa-7-azaspiro[4.4]nonyl, 1-oxa-7-azaspiro[3.5]nonyl,1-oxa-8-azaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl,1-oxa-4,9-diazaspiro[5.5]undecyl, 2-oxa-7-azaspiro[3.5]nonyl,5-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.5]nonyl,7-oxa-2-azaspiro[3.5]nonyl, 8-oxa-2-azaspiro[4.5]decyl,2,7-diazaspiro[4.4]nonyl, 1,4-dioxa-8-azaspiro[4.5]decyl,1,3,8-triazaspiro[4.5]decyl. In a fused ring heterocycle, the ringsshare one common bond. Examples of fused bicyclic heterocycles are a 4-6membered monocyclic heterocycle fused to a phenyl group, or a 4-6membered monocyclic heterocycle fused to a C₃-C₆ monocyclic cycloalkyl,or a 4-6 membered monocyclic heterocycle fused to a C₄-C₇ monocycliccycloalkenyl, or a 4-6 membered monocyclic heterocycle fused to a 4-7membered monocyclic heterocycle. Examples of fused bicyclic heterocyclesinclude, but are not limited to, 1,2-dihydrophthalazinyl,3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, chromanyl, chromenyl,isochromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, isoindolinyl,2,3-dihydrobenzo[b]thienyl, hexahydro-1H-cyclopenta[c]furanyl,3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexyl, benzopyranyl,benzothiopyranyl, indolinyl, decahydropyrrolo[3,4-b]azepinyl,2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)-yl,2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl,hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,hexahydrocyclopenta[c]pyrrol-3a(1H)-yl,hexahydro-1H-oxazolo[3,4-a]pyrazinyl,octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydroimidazo[1,5-a]pyrazinyl,octahydropyrrolo[1,2-a]pyrazinyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl,and octahydropyrrolo[3,4-c]pyrrolyl. In a bridged heterocycle, the ringsshare at least two non-adjacent atoms. Examples of such bridgedheterocycles include, but are not limited to,8-oxabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),8-azabicyclo[3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene,8-oxa-3-azabicyclo[3.2.1]octyl,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane(1-azatricyclo[3.3.1.1^(3,7)]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.1^(3,7)]decane). The nitrogen and sulfurheteroatoms in the heterocycle rings may optionally be oxidized (e.g.1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl,1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally bequaternized. Non limiting examples of the polycyclic heterocycle include6,7-dihydro-[1,3]dioxolo[4,5-]benzofuranyl.

The term “4-7 membered heterocyclyl” as used herein, means a hydrocarbonring radical of 4-7 carbon ring atoms wherein at least one carbon atomis replaced by a heteroatom(s) independently selected from the groupconsisting of O, N, and S.

The term “5-11 membered heteroaryl” as used herein, means a monocyclicheteroaryl and a bicyclic heteroaryl. The “5-6 membered heteroaryl” is afive- or six-membered ring. The five-membered ring contains two doublebonds. The five membered ring may contain one heteroatom selected from Oor S; or one, two, three, or four nitrogen atoms and optionally oneoxygen or one sulfur atom. The six-membered ring contains three doublebonds and one, two, three or four nitrogen atoms. Examples of 5-6membered monocyclic heteroaryl include, but are not limited to, furanyl,imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl,pyridazinonyl, pyridinonyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl,thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of amonocyclic heteroaryl fused to a phenyl, or a monocyclic heteroarylfused to a C₃-C₆ monocyclic cycloalkyl, or a monocyclic heteroaryl fusedto C₄-C₇ monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to amonocyclic heteroaryl, or a monocyclic heteroaryl fused to a 4-7membered monocyclic heterocycle. Representative examples of bicyclicheteroaryl groups include, but are not limited to,4H-furo[3,2-b]pyrrolyl, benzofuranyl, benzothienyl, benzoisoxazolyl,benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl,2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl,quinolinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The nitrogen atom in the heteroarylrings may optionally be oxidized and may optionally be alkylated.

The term “6-10 membered aryl”, as used herein, means a hydrocarbon ringradical containing 6-10 carbon atoms, zero heteroatoms, and one or morearomatic rings. The 6-10 membered aryl group may be a single-ring(monocyclic) or have two rings (bicyclic). The bicyclic aryl isnaphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenylfused to a monocyclic cycloalkenyl. Representative examples of 6-10membered aryl groups include, but are not limited to, phenyl, indenyl,tetrahydronaphthalenyl, dihydroindenyl (indanyl), naphthyl, and thelike.

The aryls, the cycloalkyls, the cycloalkenyls, the heterocycles, and theheteroaryls, including the exemplary rings, are optionally substitutedunless otherwise indicated; and are attached to the parent molecularmoiety through any substitutable atom contained within the ring system.

The term “heteroatom” as used herein, means a nitrogen, oxygen, andsulfur.

The term “oxo” as used herein, means a ═O group.

The term “radiolabel” means a compound of the invention in which atleast one of the atoms is a radioactive atom or a radioactive isotope,wherein the radioactive atom or isotope spontaneously emits gamma raysor energetic particles, for example alpha particles or beta particles,or positrons. Examples of such radioactive atoms include, but are notlimited to, ³H (tritium), ¹⁴C, ¹C, ¹⁵O, ¹⁸F, ³⁵S, ¹²³I, and ¹²⁵I.

A moiety is described as “substituted” when a non-hydrogen radical is inthe place of hydrogen radical of any substitutable atom of the moiety.Thus, for example, a substituted heterocycle moiety is a heterocyclemoiety in which at least one non-hydrogen radical is in the place of ahydrogen radical on the heterocycle. It should be recognized that ifthere are more than one substitution on a moiety, each non-hydrogenradical may be identical or different (unless otherwise stated).

If a moiety is described as being “optionally substituted,” the moietymay be either (1) not substituted or (2) substituted. If a moiety isdescribed as being optionally substituted with up to a particular numberof non-hydrogen radicals, that moiety may be either (1) not substituted;or (2) substituted by up to that particular number of non-hydrogenradicals or by up to the maximum number of substitutable positions onthe moiety, whichever is less. Thus, for example, if a moiety isdescribed as a heteroaryl optionally substituted with up to 3non-hydrogen radicals, then any heteroaryl with less than 3substitutable positions would be optionally substituted by up to only asmany non-hydrogen radicals as the heteroaryl has substitutablepositions. To illustrate, tetrazolyl (which has only one substitutableposition) would be optionally substituted with up to one non-hydrogenradical. To illustrate further, if an amino nitrogen is described asbeing optionally substituted with up to 2 non-hydrogen radicals, then aprimary amino nitrogen will be optionally substituted with up to 2non-hydrogen radicals, whereas a secondary amino nitrogen will beoptionally substituted with up to only 1 non-hydrogen radical.

The terms “treat”, “treating”, and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing”, and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring or developing a disease or disorder.

The phrase “therapeutically effective amount” means an amount of acompound, or a pharmaceutically acceptable salt thereof, sufficient toprevent the development of or to alleviate to some extent one or more ofthe symptoms of the condition or disorder being treated whenadministered alone or in conjunction with another therapeutic agent fortreatment in a particular subject or subject population.

The term “subject” is defined herein to refer to a human or patient. Theterms “human,” “patient,” and “subject” are used interchangeably herein.

As used herein, “Class I mutation(s)” refers to mutations whichinterfere with protein synthesis. They result in the introduction of apremature signal of termination of translation (stop codon) in the mRNA.The truncated CFTR proteins are unstable and rapidly degraded, so, thenet effect is that there is no protein at the apical membrane. Inparticular, Class I mutation(s) refers to p.Gly542X (G542X), W1282X,c.489+1G>T (621+1G>T), or c.579+1G>T (711+1G>T) mutation. Moreparticularly, Class I mutation(s) refers to G542X; or W1282X mutations.

As used herein, “Class II mutation(s)” refers to mutations which affectprotein maturation. These lead to the production of a CFTR protein thatcannot be correctly folded and/or trafficked to its site of function onthe apical membrane. In particular, Class II mutation(s) refers top.Phe508del (F508del), p.Ile507del, or p.Asn1303Lys (N1303K) mutations.More particularly, Class II mutation(s) refers to F508del or N1303Kmutations.

As used herein, “Class III mutation(s)” refers to mutations which alterthe regulation of the CFTR channel. The mutated CFTR protein is properlytrafficked and localized to the plasma membrane but cannot be activated,or it cannot function as a chloride channel. In particular, Class IIImutation(s) refers to p.Gly551Asp (G551D), G551S, R553G, G1349D, S1251N,G178R, S549N mutations. More particularly, Class III mutation(s) refersto G551D, R553G, G1349D, S1251N, G178R, or S549N mutations.

As used herein, “Class IV mutation(s)” refers to mutations which affectchloride conductance. The CFTR protein is correctly trafficked to thecell membrane but generates reduced chloride flow or a “gating defect”(most are missense mutations located within the membrane-spanningdomain). In particular, Class IV mutation(s) refers to p.Arg117His(R117H), R347P, or p.Arg334Trp (R334W) mutations.

As used herein, “Class V mutation(s)” refers to mutations which reducethe level of normally functioning CFTR at the apical membrane or resultin a “conductance defect” (for example partially aberrant splicingmutations or inefficient trafficking missense mutations). In particular,Class V mutation(s) refers to c.1210-12T[5] (5T allele), c.S3140-26A>G(3272-26A>G), c.3850-2477C>T (3849+10kbC>T) mutations.

As used herein, “Class VI mutation(s)” refers to mutations whichdecrease the stability of the CFTR which is present or which affect theregulation of other channels, resulting in inherent instability of theCFTR protein. In effect, although functional, the CFTR protein isunstable at the cell surface and it is rapidly removed and degraded bycell machinery. In particular, Class VI mutation(s) refers to RescuedF508del, 120de123, N287Y, 4326dellTC, or 4279insA mutations. Moreparticularly, Class VI mutation(s) refers to Rescued F508del mutations.

Compounds

Compounds of the invention have the general Formula (I) as describedabove.

Particular values of variable groups are as follows. Such values may beused where appropriate with any of the other values, definitions, claimsor embodiments defined hereinbefore or hereinafter.

Certain embodiments pertain to compounds of Formula (I),

wherein

-   -   A¹ is selected from the group consisting of C₃-C₇ cycloalkyl,        C₄-C₇ cycloalkenyl, and 4-7 membered heterocyclyl;    -   R¹ is selected from the group consisting of 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R¹        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are        substituted with two or more substituents independently selected        from the group consisting of R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷,        C(O)OR⁷, SO₂R7, C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NHR⁷,        N(R⁷)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R² is independently selected from the group consisting of R⁸,        OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN,        NO₂, F, Cl, Br and I;    -   n is 0 or 1;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br        and I; wherein the R³ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R⁹, OR⁹, SR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R9,        C(O)NH₂, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂,        C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆        alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with        one or more substituents independently selected from the group        consisting of OR⁰, F, Cl, Br and I;    -   R⁷, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, C₃-C₇ cycloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I;        wherein each R⁷ 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        R¹¹, OR¹¹, SR¹¹, C(O)R¹¹, OC(O)R¹¹, C(O)OR¹¹, SO₂R¹¹, C(O)NH₂,        C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH,        OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁸, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;        wherein each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br        and I;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹³, OR¹³,        SR¹³, C(O)R³, OC(O)R¹³, C(O)OR¹³, SO₂R¹³, C(O)NH₂, C(O)NHR¹³,        C(O)N(R¹³)₂, NHC(O)R¹³, NHR¹³, N(R¹³)₂, NH₂, C(O)OH, OH, oxo,        CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R¹⁴, OR¹⁴, SR¹⁴, C(O)R⁴, OC(O)R¹⁴,        C(O)OR¹⁴, SO₂R¹⁴, C(O)NH₂, C(O)NHR¹⁴, C(O)N(R¹⁴)₂, NHC(O)R¹⁴,        NHR¹⁴, N(R¹⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰, at each occurrence, is independently C₁-C₄ alkyl;    -   R¹¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered        aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁        cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹        C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one        or more substituents independently selected from the group        consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I;        wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12        membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I; R¹², at each        occurrence, is independently selected from the group consisting        of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁        cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and        5-6 membered heteroaryl;    -   R¹³, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl        is optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6        membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and    -   R¹⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered        heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   with the proviso that the compound is not        1-(3,4-dimethylphenyl)-N-(naphthalene-1-sulfonyl)cyclopentane-1-carboxamide.

In one embodiment of Formula (I), A¹ is selected from the groupconsisting of C₃-C₇ cycloalkyl, C₄-C₇ cycloalkenyl, and 4-7 memberedheterocyclyl. In another embodiment of Formula (I), A¹ is C₃-C₇cycloalkyl. In another embodiment of Formula (I), A¹ is C₄-C₇cycloalkenyl. In another embodiment of Formula (I), A¹ is 4-7 memberedheterocyclyl. In another embodiment of Formula (I), A¹ is cyclopropyl orcyclobutyl. In another embodiment of Formula (I), A¹ is cyclopropyl. Inanother embodiment of Formula (I), A¹ is cyclobutyl. In anotherembodiment of Formula (I), A¹ is cyclopentyl. In another embodiment ofFormula (I), A¹ is tetrahydropyranyl. In another embodiment of Formula(I), A¹ is piperidinyl.

In one embodiment of Formula (I), R¹ is selected from the groupconsisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; whereinthe R¹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are substituted withtwo or more substituents independently selected from the groupconsisting of R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷, C(O)OR⁷, SO₂R⁷, C(O)NH₂,C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R¹ isselected from the group consisting of 6-10 membered aryl, 5-11 memberedheteroaryl, and 4-12 membered heterocyclyl; wherein the R¹ 6-10 memberedaryl, 5-11 membered heteroaryl, and 4-12 membered heterocyclyl aresubstituted with two or more substituents independently selected fromthe group consisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, CN, F, Cl, and Br. Inanother embodiment of Formula (I), R¹ is 6-10 membered aryl; wherein theR¹ 6-10 membered aryl is substituted with two or more substituentsindependently selected from the group consisting of R⁷, OR⁷, C(O)OR⁷,N(R⁷)₂, CN, F, Cl, and Br. In another embodiment of Formula (I), R¹ is5-11 membered heteroaryl; wherein the R¹ 5-11 membered heteroaryl issubstituted with two or more substituents independently selected fromthe group consisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, andBr. In another embodiment of Formula (I), R¹ is 4-12 memberedheterocyclyl; wherein the R¹4-12 membered heterocyclyl is substitutedwith two or more substituents independently selected from the groupconsisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, and Br. Inanother embodiment of Formula (I), R¹ is phenyl; wherein the R¹ phenylis substituted with two or more substituents independently selected fromthe group consisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, andBr. In another embodiment of Formula (I), R¹ is selected from the groupconsisting of pyrazolyl, pyridinyl, quinolinyl, pyrimidinyl, andbenzo[d][1,3]dioxolyl; wherein the R¹ pyrazolyl, pyridinyl, quinolinyl,pyrimidinyl, and benzo[d][1,3]dioxolyl are substituted with two or moresubstituents independently selected from the group consisting of R⁷,OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, and Br.

In one embodiment of Formula (I), n is 0 or 1; and R² is independentlyselected from the group consisting of R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸,NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (I), n is 1; and R² is independently selected fromthe group consisting of R⁸ and C(O)OR⁸. In another embodiment of Formula(I), n is 0. In another embodiment of Formula (I), n is 1; and R² isindependently R⁸. In another embodiment of Formula (I), n is 1; and R²is independently C(O)OR⁸. In another embodiment of Formula (I), n is 1;and R² is independently R⁸; and R⁸ is independently C₁-C₆ alkyl. Inanother embodiment of Formula (I), n is 1; and R² is independentlyC(O)OR⁸; and R⁸ is independently C₁-C₆ alkyl.

In one embodiment of Formula (I), R³ is selected from the groupconsisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl,and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³ 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl are optionally substitutedwith one or more substituents independently selected from the groupconsisting of R⁹, OR⁹, SR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂,C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, F, Cl, Br and I. In another embodiment of Formula (I), R³ isselected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl,5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; wherein the R³ C₁-C₆ alkyl is optionally substituted withone or more substituents independently selected from the groupconsisting of phenyl, F, and Cl; wherein the R³ 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclylare optionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br.

In another embodiment of Formula (I), R³ is C₁-C₆ alkyl; wherein the R³C₁-C₆ alkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of phenyl, F, and Cl.In another embodiment of Formula (I), R³ is 6-10 membered aryl; whereinthe R³ 6-10 membered aryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹,OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (I), R³ is 5-11membered heteroaryl; wherein the R³ 5-11 membered heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (I), R³ is C₃-C₁₁ cycloalkyl; wherein the R³C₃-C₁₁ cycloalkyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹,OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, C1, and Br. In another embodiment of Formula (I), R³ is 4-12membered heterocyclyl; wherein the R³ 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (I), R³ is phenyl; wherein the R³ phenyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (I), R³ is napthyl; wherein the R³ napthyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (I), R³ is quinolinyl; wherein the R³ quinolinylis optionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (I), R³ is tetrahydroquinolinyl; wherein the R³tetrahydroquinolinyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹,OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (I), R³ is indazolyl;wherein the R³ indazolyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹,OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (I), R³ ispyrazolo[1,5-a]pyridinyl; wherein the R³ pyrazolo[1,5-a]pyridinyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (I), R³ is indolyl; wherein the R³ indolyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (I), R³ is benzoimidazolyl; wherein the R³benzoimidazolyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, C(O)R⁹,C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br.

In one embodiment of Formula (I), R⁴ is selected from the groupconsisting of hydrogen and C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OR¹⁰, F, Cl, Br and I. In anotherembodiment of Formula (I), R⁴ is selected from the group consisting ofhydrogen and C₁-C₆ alkyl. In another embodiment of Formula (I), R⁴ ishydrogen. In another embodiment of Formula (I), R⁴ is C₁-C₆ alkyl. Inanother embodiment of Formula (I), R⁴ is CH₃.

In one embodiment of Formula (I), R⁷, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkoxy, C₃-C₇ cycloalkyl,OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10 membered aryl,5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and4-12 membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹¹,OR¹¹, SR¹¹, C(O)R¹¹, OC(O)R¹¹, C(O)OR¹¹, SO₂R¹¹, C(O)NH₂, C(O)NHR¹¹,C(O)N(R¹¹)₂, NHC(O)R¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂,F, Cl, Br and I. In another embodiment of Formula (I), R⁷, at eachoccurrence, is independently selected from the group consisting of C₁-C₆alkyl, C₃-C₁₁ cycloalkyl, 5-11 membered heteroaryl, and 4-12 memberedheterocyclyl; wherein each R⁷ C₁-C₆ alkyl is optionally substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, OH and F; wherein each R⁷C₃-C₁₁ cycloalkyl, 5-11 membered heteroaryl, and 4-12 memberedheterocyclyl are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹¹, OR¹¹, NHR¹¹,and C(O)OR¹¹.

In one embodiment of Formula (I), R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³,OC(O)R¹³, C(O)OR¹³ SO₂R¹³, C(O)NH₂, C(O)NHR¹³, C(O)N(R¹³)₂, NHC(O)R¹³,NHR¹³, N(R¹³)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I; whereineach R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R¹⁴, OR¹⁴, SR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴,SO₂R¹⁴, C(O)NH₂, C(O)NHR¹⁴, C(O)N(R¹⁴)₂, NHC(O)R¹⁴, NHR¹⁴, N(R⁴)₂, NH₂,C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment ofFormula (I), R⁹, at each occurrence, is independently selected from thegroup consisting of C₁-C₆ alkyl, 5-11 membered heteroaryl, and 4-12membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R¹³ and F; wherein each R⁹ 5-11 memberedheteroaryl and 4-12 membered heterocyclyl is optionally substituted withone or more oxo. In another embodiment of Formula (I), R⁹, at eachoccurrence, is independently selected from the group consisting of 5-11membered heteroaryl and 4-12 membered heterocyclyl; wherein each R⁹ 5-11membered heteroaryl and 4-12 membered heterocyclyl is optionallysubstituted with one or more oxo. In another embodiment of Formula (I),R⁹, at each occurrence, is independently C₁-C₆ alkyl; wherein each R⁹C₁-C₆ alkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R¹³ and F. Inanother embodiment of Formula (I), R⁹, at each occurrence, isindependently C₁-C₆ alkyl; wherein each R⁹ C₁-C₆ alkyl is unsubstituted.

In one embodiment of Formula (I), R¹⁰, at each occurrence, isindependently C₁-C₄ alkyl.

In one embodiment of Formula (I), R¹¹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 memberedheterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; whereineach R¹¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with oneor more substituents independently selected from the group consisting ofC₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹¹ C₆-C₁₀membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In anotherembodiment of Formula (I), R¹¹, at each occurrence, is independentlyC₁-C₆ alkyl; wherein each R¹¹ C₁-C₆ alkyl is optionally substituted withC₁-C₆ alkoxy.

In one embodiment of Formula (I), R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 memberedheterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl.

In one embodiment of Formula (I), R¹³, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;wherein each R¹³ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (I), R¹³, at each occurrence, is C₆-C₁₀ memberedaryl.

In one embodiment of Formula (I), R¹⁴, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO₂, F,Cl, Br and I.

In one embodiment of Formula (I),

-   -   A¹ is selected from the group consisting of C₃-C₇ cycloalkyl and        4-7 membered heterocyclyl;    -   R¹ is selected from the group consisting of 6-10 membered aryl,        5-11 membered heteroaryl, and 4-12 membered heterocyclyl;        wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl, and        4-12 membered heterocyclyl are substituted with two or more        substituents independently selected from the group consisting of        R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, and Br;    -   R² is independently selected from the group consisting of R⁸ and        C(O)OR;    -   n is 0 or 1;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and        4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is        optionally substituted with one or more substituents        independently selected from the group consisting of phenyl, F,        and Cl; wherein the R³ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,        NO₂, Cl, and Br;    -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆        alkyl;    -   R⁷, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁷        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, OH and F; wherein each R⁷ 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl and 4-12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        R¹¹, OR¹¹, NHR¹¹, and C(O)OR¹¹;    -   R⁸ is independently C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 5-11 membered heteroaryl, and 4-12        membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R¹³ and F; wherein each R⁹ 5-11        membered heteroaryl and 4-12 membered heterocyclyl is optionally        substituted with one oxo;    -   R¹¹, at each occurrence, is independently C₁-C₆ alkyl; wherein        each R¹¹ C₁-C₆ alkyl is optionally substituted with one C₁-C₆        alkoxy; and    -   R¹³, at each occurrence, is independently C₆-C₁₀ membered aryl;    -   with the proviso that the compound is not        1-(3,4-dimethylphenyl)-N-(naphthalene-1-sulfonyl)cyclopentane-1-carboxamide.

Exemplary compounds of Formula (I) include, but are not limited to:

-   1-(5-bromo-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(propan-2-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(2,5-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,5-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethoxy-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclobutyloxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-tert-butyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-tert-butyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-6-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2,3-dimethylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-6-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclobutyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2,3-dihydro-H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(difluoromethoxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-diethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(5-cyclobutyl-2-methoxyphenyl)cyclopropane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethoxy-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-tert-butyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(2,5-dimethylphenyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[1-(methylamino)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(2-ethoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(oxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(2-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-{[(2R)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-methylphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxycyclobutyl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-{[(2R)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[3-(dimethylamino)-6-(2-methylpropoxy)pyridin-2-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(dimethylamino)-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2S)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2S)-2-methoxypropoxy]-5-methylphenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2R)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2R)-2-methoxypropoxy]-5-methylphenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-4-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclopentyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-[5-(butan-2-yl)-2-methoxyphenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-{2-methoxy-5-[(oxolan-3-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-5-(trifluoromethoxy)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-5-(trifluoromethoxy)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   methyl    1-(4-methoxy-3-{1-[(quinoline-5-sulfonyl)carbamoyl]cyclopropyl}phenyl)cyclopropane-1-carboxylate;-   methyl    4-methoxy-3-{1-[(quinoline-5-sulfonyl)carbamoyl]cyclopropyl}benzoate;-   methyl    4-methoxy-3-{1-[(naphthalene-1-sulfonyl)carbamoyl]cyclopropyl}benzoate;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2,3-dimethylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclobutyl-5-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclobutyl-5-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(hydroxymethyl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(methoxymethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2,3-dimethylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-chloro-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methoxy-2-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methoxy-2-propylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-6-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,5-dimethylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-4-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-3-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(4-cyclobutyl-2,6-dimethoxyphenyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(5-ethyl-2-methoxyphenyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-(6-methoxy-2,3-dimethylphenyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   1-(2,5-dimethylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-6-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-[2-(methylamino)quinoline-5-sulfonyl]cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2,2,2-trifluoro-1-methoxyethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxyethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(3-methyloxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-(2-{[(2S)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(2-ethoxypropan-2-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-ethylphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxycyclobutyl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-methylphenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(difluoromethoxy)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-ethylphenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-{[(2S)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-ethoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-ethoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(1-ethoxy-2-methylpropan-2-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(1-ethoxy-2-methylpropan-2-yl)-2-methoxyphenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(dimethylamino)-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(2,3-dihydro-1H-indene-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   methyl    5-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}-4-methoxythiophene-3-carboxylate;-   1-(2,4-dichlorophenyl)-N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[2-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[4-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[3-(trifluoromethyl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[4-(2-oxopyrrolidin-1-yl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[5-(1,2-oxazol-5-yl)thiophene-2-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[4-(pyrrolidine-1-sulfonyl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)-N-methylcyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-{4-[(propan-2-yl)oxy]benzene-1-sulfonyl}cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[6-(morpholin-4-yl)pyridine-3-sulfonyl]cyclopropane-1-carboxamide;-   benzyl    4-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;-   1-(2,4-dichlorophenyl)-N-(4-methoxybenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(3,4-dimethoxybenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(3-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(naphthalene-2-sulfonyl)cyclopropane-1-carboxamide;-   N-(cyclopropanesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(3,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(1,1-dioxo-1λ⁶-thiolane-3-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(4-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-cyano-5-fluorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(pyridine-3-sulfonyl)cyclopropane-1-carboxamide;-   N-(6-chloropyridine-3-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   methyl    5-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}furan-2-carboxylate;-   N-(5-bromothiophene-2-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[3-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   methyl    2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoate;-   methyl    4-chloro-2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoate;-   2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoic    acid;-   4-chloro-2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoic    acid;-   benzyl    4-{[1-(3,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;-   1-(2,4-dichlorophenyl)-N-(piperidine-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1-acetylpiperidine-4-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[1-(3-phenylpropanoyl)piperidine-4-sulfonyl]cyclopropane-1-carboxamide;-   tert-butyl    4-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;-   1-(2,4-dichlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(3,4-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopentane-1-carboxamide;-   1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   4-(5-methoxy-2-methylphenyl)-1-methyl-N-(quinoline-5-sulfonyl)piperidine-4-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-(5-cyano-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyano-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(3,5-dichloro-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(trifluoromethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(2,2,2-trifluoroethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(propane-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(3-chloropropane-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(propane-2-sulfonyl)cyclopropane-1-carboxamide;-   1-(3,4-dichlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   N-(pentane-3-sulfonyl)-1-phenylcyclopropane-1-carboxamide;-   1-(3,4-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclobutane-1-carboxamide;-   1-[2-methoxy-6-(1-methyl-1H-pyrazol-4-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-6-methylpyridin-2-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-6-methylpyridin-2-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-6-methylpyridin-2-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,5-dimethylphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(3-methoxyoxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)    cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(3-²H)oxetan-3-yl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-(2-ethyl-6-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethyl-6-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-[2-(dimethylamino)quinoline-5-sulfonyl]-1-(2-ethoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-{5-bromo-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide    1-{5-bromo-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-chloro-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide-   1-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(propan-2-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(propan-2-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclopropyl-5-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(propan-2-yl)oxy]-5-(pyrrolidin-1-yl)pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-methylquinoline-5-sulfonyl)-1-{2-[(propan-2-yl)xy]-5-(pyrrolidin-1-yl)pyridin-3-yl}cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{2-[(propan-2-yl)oxy]-5-(pyrrolidin-1-yl)pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}cyclopropane-1-carboxamide;-   1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-ethoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-ethoxypyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-ethylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-ethylpyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-[1-(methoxymethyl)cyclopropyl]-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dimethoxypyrimidin-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(naphthalene-1-sulfonyl)-1-{2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-chloro-2-methoxypyridin-4-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide.-   1-(5-chloro-2-methoxypyridin-4-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(morpholin-4-yl)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-methylpyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylpyridin-4-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-5-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-ethyl-5-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethyl-5-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[6-(dimethylamino)-2-methoxypyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-ethylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-ethylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-4-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-4-methylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(1,2,34-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-methylquinoline-5-sulfonyl)-1-[2-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-5-methylpyridin-2-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methoxy-2-(2-methoxyethoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methoxyethoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxyethoxy)pyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-ethylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-ethylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-ethylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methoxyethoxy)-5-methylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-(dimethylamino)-6-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methoxyethoxy)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-(2-methoxyethoxy)-5-methylpyridin-3-yl]cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-5-methylpyridin-2-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-5-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-ethylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-fluoro-5-methylpyridin-4-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2-methylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxyethoxy)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dimethoxypyrimidin-5-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-chloro-5-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(2,2-difluoroethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-fluoro-5-methylpyridin-4-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(2,2-difluoroethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dimethoxypyrimidin-5-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-amino-2-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-chloro-2-fluoropyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(hydroxymethyl)-2-[(propan-2-yl)xy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;    and pharmaceutically acceptable salts thereof.

Certain embodiments pertain to compounds of Formula (II),

wherein

-   -   R¹ is selected from the group consisting of 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R¹        6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are        substituted with two or more substituents independently selected        from the group consisting of R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷,        C(O)OR⁷, SO₂R⁷, C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NHR⁷,        N(R⁷)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R² is independently selected from the group consisting of        hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,        C(O)OH, OH, CN, NO₂, F, Cl, Br and I;    -   n is 0 or 1;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br        and I; wherein the R³ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R⁹, OR⁹, SR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹,        C(O)NH₂, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂,        C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆        alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with        one or more substituents independently selected from the group        consisting of OR¹⁰, F, Cl, Br and I;    -   R⁷, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, C₃-C₇ cycloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I;        wherein each R⁷ 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        R¹¹, OR¹¹, SR¹¹, C(O)R¹¹, OC(O)R¹¹, C(O)OR¹¹, SO₂R¹¹, C(O)NH₂,        C(O)NHR¹¹, C(O)N(R¹¹)₂, NHC(O)R¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH,        OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁸, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;        wherein each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br        and I;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹³, OR³,        SR¹³, C(O)R³, OC(O)R¹³, C(O)OR¹³, SO₂R¹³, C(O)NH₂, C(O)NHR³,        C(O)N(R³)₂, NHC(O)R¹³, NHR¹³, N(R³)₂, NH₂, C(O)OH, OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered aryl, 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and        4-12 membered heterocyclyl is optionally substituted with one or        more substituents independently selected from the group        consisting of R⁴, OR⁴, SR¹⁴ C(O)R¹⁴, OC(O)R¹⁴, C(O)OR⁴, SO₂R¹⁴,        C(O)NH₂, C(O)NHR⁴, C(O)N(R¹⁴)₂, NHC(O)R⁴, NHR⁴, N(R⁴)₂, NH₂,        C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰, at each occurrence, is independently C₁-C₄ alkyl;    -   R¹¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered        aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁        cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹        C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one        or more substituents independently selected from the group        consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I;        wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12        membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered        aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁        cycloalkenyl, and 5-6 membered heteroaryl;    -   R¹³, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl        is optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6        membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and    -   R¹⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered        heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I.

In one embodiment of Formula (II), R¹ is selected from the groupconsisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; whereinthe R¹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are substituted withtwo or more substituents independently selected from the groupconsisting of R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷, C(O)OR⁷, SO₂R⁷, C(O)NH₂,C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R¹ isselected from the group consisting of 6-10 membered aryl, 5-11 memberedheteroaryl, and 4-12 membered heterocyclyl; wherein the R¹ 6-10 memberedaryl, 5-11 membered heteroaryl, and 4-12 membered heterocyclyl aresubstituted with two or more substituents independently selected fromthe group consisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, CN, F, Cl, and Br. Inanother embodiment of Formula (II), R¹ is 6-10 membered aryl; whereinthe R¹ 6-10 membered aryl is substituted with two or more substituentsindependently selected from the group consisting of R⁷, OR⁷, C(O)OR⁷,N(R⁷)₂, CN, F, Cl, and Br. In another embodiment of Formula (II), R¹ is5-11 membered heteroaryl; wherein the R¹ 5-11 membered heteroaryl issubstituted with two or more substituents independently selected fromthe group consisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, andBr. In another embodiment of Formula (II), R¹ is 4-12 memberedheterocyclyl; wherein the R¹ 4-12 membered heterocyclyl is substitutedwith two or more substituents independently selected from the groupconsisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, and Br. Inanother embodiment of Formula (II), R¹ is phenyl; wherein the R¹ phenylis substituted with two or more substituents independently selected fromthe group consisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, andBr. In another embodiment of Formula (II), R¹ is selected from the groupconsisting of pyrazolyl, pyridinyl, quinolinyl, pyrimidinyl, andbenzo[d][1,3]dioxolyl; wherein the R¹ pyrazolyl, pyridinyl, quinolinyl,pyrimidinyl, and benzo[d][1,3]dioxolyl are substituted with two or moresubstituents independently selected from the group consisting of R⁷,OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, and Br.

In one embodiment of Formula (II), n is 0 or 1; and R² is independentlyselected from the group consisting of R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸,NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (II), n is 1; and R² is independently selectedfrom the group consisting of R⁸ and C(O)OR⁸. In another embodiment ofFormula (II), n is 0. In another embodiment of Formula (II), n is 1; andR² is independently R⁸. In another embodiment of Formula (II), n is 1;and R² is independently C(O)OR⁸. In another embodiment of Formula (II),n is 1; and R² is independently R⁸; and R⁸ is independently C₁-C₆ alkyl.In another embodiment of Formula (II), n is 1; and R² is independentlyC(O)OR⁸; and R⁸ is independently C₁-C₆ alkyl.

In one embodiment of Formula (II), R³ is selected from the groupconsisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl,and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³ 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl are optionally substitutedwith one or more substituents independently selected from the groupconsisting of R⁹, OR⁹, SR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂,C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, F, Cl, Br and I. In another embodiment of Formula (II), R³ isselected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl,5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; wherein the R³ C₁-C₆ alkyl is optionally substituted withone or more substituents independently selected from the groupconsisting of phenyl, F, and Cl; wherein the R³ 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclylare optionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br.

In another embodiment of Formula (II), R³ is C₁-C₆ alkyl; wherein the R³C₁-C₆ alkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of phenyl, F, and Cl.In another embodiment of Formula (II), R³ is 6-10 membered aryl; whereinthe R³ 6-10 membered aryl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹,OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (II), R³ is 5-11membered heteroaryl; wherein the R³ 5-11 membered heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (II), R³ is C₃-C₁₁ cycloalkyl; wherein the R³C₃-C₁ cycloalkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, C(O)R⁹,C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br.In another embodiment of Formula (II), R³ is 4-12 membered heterocyclyl;wherein the R³ 4-12 membered heterocyclyl is optionally substituted withone or more substituents independently selected from the groupconsisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂,C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In another embodiment of Formula(II), R³ is phenyl; wherein the R³ phenyl is optionally substituted withone or more substituents independently selected from the groupconsisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂,C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In another embodiment of Formula(II), R³ is napthyl; wherein the R³ napthyl is optionally substitutedwith one or more substituents independently selected from the groupconsisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂,C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In another embodiment of Formula(II), R³ is quinolinyl; wherein the R³ quinolinyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂,NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In another embodiment ofFormula (II), R³ is tetrahydroquinolinyl; wherein the R³tetrahydroquinolinyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹,OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (II), R³ is indazolyl;wherein the R³ indazolyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹,OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (II), R³ ispyrazolo[1,5-a]pyridinyl; wherein the R³ pyrazolo[1,5-a]pyridinyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (II), R³ is indolyl; wherein the R³ indolyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (II), R³ is benzoimidazolyl; wherein the R³benzoimidazolyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, C(O)R⁹,C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br.

In one embodiment of Formula (II), R⁴ is selected from the groupconsisting of hydrogen and C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OR¹⁰, F, Cl, Br and I. In anotherembodiment of Formula (II), R⁴ is selected from the group consisting ofhydrogen and C₁-C₆ alkyl. In another embodiment of Formula (II), R⁴ ishydrogen. In another embodiment of Formula (II), R⁴ is C₁-C₆ alkyl. Inanother embodiment of Formula (II), R⁴ is CH₃.

In one embodiment of Formula (II), R⁷, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkoxy, C₃-C₇ cycloalkyl,OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10 membered aryl,5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and4-12 membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹¹,OR¹¹, SR¹¹, C(O)R¹¹, OC(O)R¹¹, C(O)OR¹¹, SO₂R¹¹, C(O)NH₂, C(O)NHR¹¹,C(O)N(R¹¹)₂, NHC(O)R¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂,F, Cl, Br and I. In another embodiment of Formula (II), R⁷, at eachoccurrence, is independently selected from the group consisting of C₁-C₆alkyl, C₃-C₁₁ cycloalkyl, 5-11 membered heteroaryl, and 4-12 memberedheterocyclyl; wherein each R⁷ C₁-C₆ alkyl is optionally substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, OH and F; wherein each R⁷C₃-C₁₁ cycloalkyl, 5-11 membered heteroaryl, and 4-12 memberedheterocyclyl are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹¹, OR¹¹, NHR¹¹,and C(O)OR¹¹.

In one embodiment of Formula (II), R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³,OC(O)R¹³, C(O)OR¹³, SO₂R¹³, C(O)NH₂, C(O)NHR¹³, C(O)N(R¹³)₂, NHC(O)R¹³,NHR¹³, N(R¹³)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I; whereineach R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R¹⁴, OR¹⁴, SR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴,SO₂R⁴, C(O)NH₂, C(O)NHR⁴, C(O)N(R⁴)₂, NHC(O)R⁴, NHR⁴, N(R¹⁴)₂, NH₂,C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment ofFormula (II), R⁹, at each occurrence, is independently selected from thegroup consisting of C₁-C₆ alkyl, 5-11 membered heteroaryl, and 4-12membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R¹³, and F; wherein each R⁹ 5-11 memberedheteroaryl and 4-12 membered heterocyclyl is optionally substituted withone or more oxo. In another embodiment of Formula (II), R⁹, at eachoccurrence, is independently selected from the group consisting of 5-11membered heteroaryl and 4-12 membered heterocyclyl; wherein each R⁹ 5-11membered heteroaryl and 4-12 membered heterocyclyl is optionallysubstituted with one or more oxo. In another embodiment of Formula (II),R⁹, at each occurrence, is independently C₁-C₆ alkyl; wherein each R⁹C₁-C₆ alkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R¹³ and F. Inanother embodiment of Formula (II), R⁹, at each occurrence, isindependently C₁-C₆ alkyl; wherein each R⁹ C₁-C₆ alkyl is unsubstituted.

In one embodiment of Formula (II), R¹⁰, at each occurrence, isindependently C₁-C₄ alkyl.

In one embodiment of Formula (II), R¹¹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 memberedheterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; whereineach R¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with oneor more substituents independently selected from the group consisting ofC₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹ C₆-C₁₀membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In anotherembodiment of Formula (II), R¹, at each occurrence, is independentlyC₁-C₆ alkyl; wherein each R¹¹ C₁-C₆ alkyl is optionally substituted withC₁-C₆ alkoxy.

In one embodiment of Formula (II), R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 memberedheterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl.

In one embodiment of Formula (II), R¹³, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;wherein each R¹³ C₆-C_(1I) membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclylis optionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (II), R¹³, at each occurrence, is C₆-C_(1I)membered aryl.

In one embodiment of Formula (II), R¹⁴, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO₂, F,Cl, Br and I.

In one embodiment of Formula (II),

-   -   R¹ is selected from the group consisting of 6-10 membered aryl,        5-11 membered heteroaryl, and 4-12 membered heterocyclyl;        wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl, and        4-12 membered heterocyclyl are substituted with two or more        substituents independently selected from the group consisting of        R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, and Br;    -   R² is independently selected from the group consisting of R⁸ and        C(O)OR;    -   n is 0 or 1;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and        4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is        optionally substituted with one or more substituents        independently selected from the group consisting of phenyl, F,        and Cl; wherein the R³ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,        NO₂, Cl, and Br;    -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆        alkyl;    -   R⁷, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁷        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, OH and F; wherein each R⁷ 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl and 4-12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        R¹¹, OR¹¹, NHR¹¹, and C(O)OR¹¹;    -   R⁸ is independently C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 5-11 membered heteroaryl, and 4-12        membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl, is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹³ and F;        wherein each R⁹ 5-11 membered heteroaryl, and 4-12 membered        heterocyclyl is optionally substituted with one oxo;    -   R¹¹, at each occurrence, is independently C₁-C₆ alkyl; wherein        each R¹¹ C₁-C₆ alkyl is optionally substituted with one C₁-C₆        alkoxy; and    -   R¹³, at each occurrence, is independently C₆-C₁₀ membered aryl.

Exemplary compounds of Formula (II) include, but are not limited to:

-   1-(5-bromo-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(propan-2-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-(2,5-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,5-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethoxy-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclobutyloxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-tert-butyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-tert-butyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-6-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2,3-dimethylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-6-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclobutyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2,3-dihydro-H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(difluoromethoxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-diethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(5-cyclobutyl-2-methoxyphenyl)cyclopropane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethoxy-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-tert-butyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(2,5-dimethylphenyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[1-(methylamino)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(2-ethoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(oxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(2-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-{[(2R)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-methylphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxycyclobutyl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-{[(2R)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[3-(dimethylamino)-6-(2-methylpropoxy)pyridin-2-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(dimethylamino)-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2S)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2S)-2-methoxypropoxy]-5-methylphenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2R)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2R)-2-methoxypropoxy]-5-methylphenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-4-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(oxolan-3-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-5-(trifluoromethoxy)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-5-(trifluoromethoxy)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   methyl    1-(4-methoxy-3-{1-[(quinoline-5-sulfonyl)carbamoyl]cyclopropyl}phenyl)cyclopropane-1-carboxylate;-   methyl    4-methoxy-3-{1-[(quinoline-5-sulfonyl)carbamoyl]cyclopropyl}benzoate;-   methyl    4-methoxy-3-{1-[(naphthalene-1-sulfonyl)carbamoyl]cyclopropyl}benzoate;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2,3-dimethylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclobutyl-5-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclobutyl-5-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(hydroxymethyl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(methoxymethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2,3-dimethylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-chloro-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methoxy-2-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methoxy-2-propylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-6-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-4-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-3-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(4-cyclobutyl-2,6-dimethoxyphenyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(5-ethyl-2-methoxyphenyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-(6-methoxy-2,3-dimethylphenyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   1-(2,5-dimethylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-6-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-[2-(methylamino)quinoline-5-sulfonyl]cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2,2,2-trifluoro-1-methoxyethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxyethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(3-methyloxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-(2-{[(2S)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(2-ethoxypropan-2-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-ethylphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxycyclobutyl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-methylphenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(difluoromethoxy)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-ethylphenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-{[(2S)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-ethoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-ethoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(1-ethoxy-2-methylpropan-2-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(1-ethoxy-2-methylpropan-2-yl)-2-methoxyphenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(dimethylamino)-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(2,3-dihydro-1H-indene-5-sulfonyl)cyclopropane-1-carboxamide-   N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   methyl    5-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}-4-methoxythiophene-3-carboxylate;-   1-(2,4-dichlorophenyl)-N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)cyclopropane-1-carboxamide-   1-(2,4-dichlorophenyl)-N-[2-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[4-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[3-(trifluoromethyl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[4-(2-oxopyrrolidin-1-yl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[5-(1,2-oxazol-5-yl)thiophene-2-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[4-(pyrrolidine-1-sulfonyl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)-N-methylcyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-{4-[(propan-2-yl)oxy]benzene-1-sulfonyl}cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[6-(morpholin-4-yl)pyridine-3-sulfonyl]cyclopropane-1-carboxamide;-   benzyl    4-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate-   1-(2,4-dichlorophenyl)-N-(4-methoxybenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(3,4-dimethoxybenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(3-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(naphthalene-2-sulfonyl)cyclopropane-1-carboxamide;-   N-(cyclopropanesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(3,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(1,1-dioxo-1λ⁶-thiolane-3-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(4-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-cyano-5-fluorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(pyridine-3-sulfonyl)cyclopropane-1-carboxamide;-   N-(6-chloropyridine-3-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   methyl    5-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}furan-2-carboxylate;-   N-(5-bromothiophene-2-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[3-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   methyl    2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoate;-   methyl    4-chloro-2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoate;-   2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoic    acid;-   4-chloro-2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoic    acid;-   benzyl    4-{[1-(3,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;-   1-(2,4-dichlorophenyl)-N-(piperidine-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1-acetylpiperidine-4-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[1-(3-phenylpropanoyl)piperidine-4-sulfonyl]cyclopropane-1-carboxamide;-   tert-butyl    4-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;-   1-(2,4-dichlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-(5-cyano-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyano-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(3,5-dichloro-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(trifluoromethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(2,2,2-trifluoroethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(propane-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(3-chloropropane-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(propane-2-sulfonyl)cyclopropane-1-carboxamide;-   1-(3,4-dichlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   N-(pentane-3-sulfonyl)-1-phenylcyclopropane-1-carboxamide;    1-[2-methoxy-6-(1-methyl-1H-pyrazol-4-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-6-methylpyridin-2-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-6-methylpyridin-2-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-6-methylpyridin-2-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,5-dimethylphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(3-methoxyoxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(3-²H)oxetan-3-yl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-(2-ethyl-6-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethyl-6-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-[2-(dimethylamino)quinoline-5-sulfonyl]-1-(2-ethoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-{5-bromo-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide    1-{5-bromo-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-chloro-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide-   1-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(propan-2-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(propan-2-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclopropyl-5-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide:-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(propan-2-yl)oxy]-5-(pyrrolidin-1-yl)pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-methylquinoline-5-sulfonyl)-1-{2-[(propan-2-yl)xy]-5-(pyrrolidin-1-yl)pyridin-3-yl}cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{2-[(propan-2-yl)oxy]-5-(pyrrolidin-1-yl)pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}cyclopropane-1-carboxamide;-   1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-ethoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-ethoxypyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-ethylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-ethylpyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-[1-(methoxymethyl)cyclopropyl]-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dimethoxypyrimidin-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(naphthalene-1-sulfonyl)-1-{2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-chloro-2-methoxypyridin-4-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide.-   1-(5-chloro-2-methoxypyridin-4-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(morpholin-4-yl)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-methylpyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylpyridin-4-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-5-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-ethyl-5-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethyl-5-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[6-(dimethylamino)-2-methoxypyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-ethylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-ethylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-4-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-4-methylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(1,2,34-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-methylquinoline-5-sulfonyl)-1-[2-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-5-methylpyridin-2-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methoxy-2-(2-methoxyethoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methoxyethoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxyethoxy)pyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-ethylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-ethylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-ethylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methoxyethoxy)-5-methylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-(dimethylamino)-6-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methoxyethoxy)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-(2-methoxyethoxy)-5-methylpyridin-3-yl]cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-5-methylpyridin-2-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-5-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-ethylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-fluoro-5-methylpyridin-4-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2-methylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxyethoxy)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dimethoxypyrimidin-5-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-chloro-5-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(2,2-difluoroethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-fluoro-5-methylpyridin-4-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(2,2-difluoroethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dimethoxypyrimidin-5-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-amino-2-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-chloro-2-fluoropyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(hydroxymethyl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;    and pharmaceutically acceptable salts thereof.

Certain embodiments pertain to compounds of Formula (III),

wherein

-   -   R¹ is selected from the group consisting of 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R¹6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are        substituted with two or more substituents independently selected        from the group consisting of R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷,        C(O)OR⁷, SO₂R⁷, C(O)NH₂, C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NHR⁷,        N(R⁷)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R² is independently selected from the group consisting of        hydrogen, R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸, NHR⁸, N(R⁸)₂, NH₂,        C(O)OH, OH, CN, NO₂, F, Cl, Br and I;    -   n is 0 or 1;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆        alkenyl, and C₂-C₆ alkynyl are optionally substituted with one        or more substituents independently selected from the group        consisting of C₁-C₆ alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br        and I; wherein the R³ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12        membered heterocyclyl are optionally substituted with one or        more substituents independently selected from the group        consisting of R⁹, OR⁹, SR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹,        C(O)NH₂, C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂,        C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆        alkyl; wherein the R⁴ C₁-C₆ alkyl is optionally substituted with        one or more substituents independently selected from the group        consisting of OR¹⁰, F, Cl, Br and I;    -   R⁷, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆        alkoxy, C₃-C₇ cycloalkyl, OH, oxo, CN, NO₂, F, Cl, Br and I;        wherein each R⁷ 6-10 membered aryl, 5-11 membered heteroaryl,        C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        R¹¹, OR¹¹, SR¹¹, C(O)R¹¹, OC(O)R¹¹, C(O)OR¹¹, SO₂R¹¹, C(O)NH₂,        C(O)NHR¹¹, C(O)N(R₁₁)₂, NHC(O)R¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH,        OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R⁸, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl;        wherein each R⁸ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹², OR¹²,        C(O)OR¹², NHR¹², N(R¹²)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br        and I;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,        C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; wherein        each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹³, OR¹³,        SR¹³, C(O)R³, OC(O)R¹³, C(O)OR¹³, SO₂R¹³, C(O)NH₂, C(O)NHR¹³,        C(O)N(R¹³)₂, NHC(O)R¹³, NHR¹³, N(R¹³)₂, NH₂, C(O)OH, OH, oxo,        CN, NO₂, F, Cl, Br and I; wherein each R⁹ 6-10 membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of R¹⁴, OR¹⁴, SR¹⁴, C(O)R⁴, OC(O)R⁴,        C(O)OR⁴, SO₂R¹⁴, C(O)NH₂, C(O)NHR⁴, C(O)N(R⁴)₂, NHC(O)R⁴, NHR⁴,        N(R⁴)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I;    -   R¹⁰, at each occurrence, is independently C₁-C₄ alkyl;    -   R¹¹, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered        aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁        cycloalkenyl, and 5-6 membered heteroaryl; wherein each R¹¹        C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with one        or more substituents independently selected from the group        consisting of C₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I;        wherein each R¹¹ C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12        membered heterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered        heteroaryl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I;    -   R¹², at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, C₆-C₁₀ membered        aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁        cycloalkenyl, and 5-6 membered heteroaryl;    -   R¹³, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl        is optionally substituted with one or more substituents        independently selected from the group consisting of OH, oxo, CN,        NO₂, F, Cl, Br and I; wherein each R¹³ C₆-C₁₀ membered aryl,        5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁        cycloalkenyl, and 4-12 membered heterocyclyl is optionally        substituted with one or more substituents independently selected        from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6        membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I; and    -   R¹⁴, at each occurrence, is independently selected from the        group consisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;        wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl        is optionally substituted with one or more substituents        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₆ alkoxy, 5-6 membered heteroaryl, 4-12 membered        heterocyclyl, OH, oxo, CN, NO₂, F, Cl, Br and I.

In one embodiment of Formula (III), R¹ is selected from the groupconsisting of 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl; whereinthe R¹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl are substituted withtwo or more substituents independently selected from the groupconsisting of R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷, C(O)OR⁷, SO₂R⁷, C(O)NH₂,C(O)NHR⁷, C(O)N(R⁷)₂, NHC(O)R⁷, NHR⁷, N(R⁷)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R¹ isselected from the group consisting of 6-10 membered aryl, 5-11 memberedheteroaryl, and 4-12 membered heterocyclyl; wherein the R¹ 6-10 memberedaryl, 5-11 membered heteroaryl, and 4-12 membered heterocyclyl aresubstituted with two or more substituents independently selected fromthe group consisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, CN, F, Cl, and Br. Inanother embodiment of Formula (III), R¹ is 6-10 membered aryl; whereinthe R¹ 6-10 membered aryl is substituted with two or more substituentsindependently selected from the group consisting of R⁷, OR⁷, C(O)OR⁷,N(R⁷)₂, CN, F, Cl, and Br. In another embodiment of Formula (III), R¹ is5-11 membered heteroaryl; wherein the R¹ 5-11 membered heteroaryl issubstituted with two or more substituents independently selected fromthe group consisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, andBr. In another embodiment of Formula (III), R¹ is 4-12 memberedheterocyclyl; wherein the R¹4-12 membered heterocyclyl is substitutedwith two or more substituents independently selected from the groupconsisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, and Br. Inanother embodiment of Formula (III), R¹ is phenyl; wherein the R¹ phenylis substituted with two or more substituents independently selected fromthe group consisting of R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, andBr. In another embodiment of Formula (III), R¹ is selected from thegroup consisting of pyrazolyl, pyridinyl, quinolinyl, pyrimidinyl, andbenzo[d][1,3]dioxolyl; wherein the R¹ pyrazolyl, pyridinyl, quinolinyl,pyrimidinyl, and benzo[d][1,3]dioxolyl are substituted with two or moresubstituents independently selected from the group consisting of R⁷,OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, and Br.

In one embodiment of Formula (III), n is 0 or 1; and R² is independentlyselected from the group consisting of R⁸, OR⁸, C(O)R⁸, C(O)OR⁸, SO₂R⁸,NHR⁸, N(R⁸)₂, NH₂, C(O)OH, OH, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (III), n is 1; and R² is independently selectedfrom the group consisting of R⁸ and C(O)OR⁸. In another embodiment ofFormula (III), n is 0. In another embodiment of Formula (III), n is 1;and R² is independently R⁸. In another embodiment of Formula (III), n is1; and R² is independently C(O)OR⁸. In another embodiment of Formula(III), n is 1; and R² is independently R⁸; and R⁸ is independently C₁-C₆alkyl. In another embodiment of Formula (III), n is 1; and R² isindependently C(O)OR⁸; and R⁸ is independently C₁-C₆ alkyl.

In one embodiment of Formula (III), R³ is selected from the groupconsisting of C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, 6-10 memberedaryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl,and 4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are optionally substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkoxy, phenyl, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein the R³ 6-10membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkenyl, and 4-12 membered heterocyclyl are optionally substitutedwith one or more substituents independently selected from the groupconsisting of R⁹, OR⁹, SR⁹, C(O)R⁹, OC(O)R⁹, C(O)OR⁹, SO₂R⁹, C(O)NH₂,C(O)NHR⁹, C(O)N(R⁹)₂, NHC(O)R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, F, Cl, Br and I. In another embodiment of Formula (III), R³ isselected from the group consisting of C₁-C₆ alkyl, 6-10 membered aryl,5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 memberedheterocyclyl; wherein the R³ C₁-C₆ alkyl is optionally substituted withone or more substituents independently selected from the groupconsisting of phenyl, F, and Cl; wherein the R³ 6-10 membered aryl, 5-11membered heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclylare optionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br.

In another embodiment of Formula (III), R³ is C₁-C₆ alkyl; wherein theR³ C₁-C₆ alkyl is optionally substituted with one or more substituentsindependently selected from the group consisting of phenyl, F, and Cl.In another embodiment of Formula (III), R³ is 6-10 membered aryl;wherein the R³ 6-10 membered aryl is optionally substituted with one ormore substituents independently selected from the group consisting ofR⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (III), R³ is 5-11membered heteroaryl; wherein the R³ 5-11 membered heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (III), R³ is C₃-C₁₁ cycloalkyl; wherein the R³C₃-C₁₁ cycloalkyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹,OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (III), R³ is 4-12membered heterocyclyl; wherein the R³ 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (III), R³ is phenyl; wherein the R³ phenyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (III), R³ is napthyl; wherein the R³ napthyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (III), R³ is quinolinyl; wherein the R³ quinolinylis optionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (III), R³ is tetrahydroquinolinyl; wherein the R³tetrahydroquinolinyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R⁹,OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (III), R³ isindazolyl; wherein the R³ indazolyl is optionally substituted with oneor more substituents independently selected from the group consisting ofR⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,NO₂, Cl, and Br. In another embodiment of Formula (III), R³ ispyrazolo[1,5-a]pyridinyl; wherein the R³ pyrazolo[1,5-a]pyridinyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (III), R³ is indolyl; wherein the R³ indolyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R⁹, OR⁹, C(O)R⁹, C(O)OR⁹, SO₂R⁹,NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br. In anotherembodiment of Formula (III), R³ is benzoimidazolyl; wherein the R³benzoimidazolyl is optionally substituted with one or more substituentsindependently selected from the group consisting of R⁹, OR⁹, C(O)R⁹,C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, Cl, and Br.

In one embodiment of Formula (III), R⁴ is selected from the groupconsisting of hydrogen and C₁-C₆ alkyl; wherein the R⁴ C₁-C₆ alkyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OR¹⁰, F, Cl, Br and I. In anotherembodiment of Formula (III), R⁴ is selected from the group consisting ofhydrogen and C₁-C₆ alkyl. In another embodiment of Formula (III), R⁴ ishydrogen. In another embodiment of Formula (III), R⁴ is C₁-C₆ alkyl. Inanother embodiment of Formula (III), R⁴ is CH₃.

In one embodiment of Formula (III), R⁷, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁷ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkoxy, C₃-C₇ cycloalkyl,OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R⁷ 6-10 membered aryl,5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and4-12 membered heterocyclyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹¹,OR¹¹, SR¹¹, C(O)R¹¹, OC(O)R¹¹, C(O)OR¹¹, SO₂R¹¹, C(O)NH₂, C(O)NHR¹¹,C(O)N(R¹¹)₂, NHC(O)R¹¹, NHR¹¹, N(R¹¹)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂,F, Cl, Br and I. In another embodiment of Formula (III), R⁷, at eachoccurrence, is independently selected from the group consisting of C₁-C₆alkyl, C₃-C₁₁ cycloalkyl, 5-11 membered heteroaryl, and 4-12 memberedheterocyclyl; wherein each R⁷ C₁-C₆ alkyl is optionally substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, OH and F; wherein each R⁷C₃-C₁₁ cycloalkyl, 5-11 membered heteroaryl, and 4-12 memberedheterocyclyl are optionally substituted with one or more substituentsindependently selected from the group consisting of R¹¹, OR¹¹, NHR¹¹,and C(O)OR¹¹.

In one embodiment of Formula (III), R⁹, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R⁹ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of R¹³, OR¹³, SR¹³, C(O)R¹³,OC(O)R¹³, C(O)OR¹³ SO₂R¹³, C(O)NH₂, C(O)NHR¹³, C(O)N(R¹³)₂, NHC(O)R¹³,NHR¹³, N(R¹³)₂, NH₂, C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I; whereineach R⁹ 6-10 membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl,C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R¹⁴, OR¹⁴, SR¹⁴, C(O)R¹⁴, OC(O)R¹⁴, C(O)OR¹⁴,SO₂R¹⁴, C(O)NH₂, C(O)NHR¹⁴, C(O)N(R¹⁴)₂, NHC(O)R¹⁴, NHR¹⁴, N(R⁴)₂, NH₂,C(O)OH, OH, oxo, CN, NO₂, F, Cl, Br and I. In another embodiment ofFormula (III), R⁹, at each occurrence, is independently selected fromthe group consisting of C₁-C₆ alkyl, 5-11 membered heteroaryl, and 4-12membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of R¹³, and F; wherein each R⁹ 5-11 memberedheteroaryl and 4-12 membered heterocyclyl is optionally substituted withone or more oxo. In another embodiment of Formula (III), R⁹, at eachoccurrence, is independently selected from the group consisting of 5-11membered heteroaryl and 4-12 membered heterocyclyl; wherein each R⁹ 5-11membered heteroaryl and 4-12 membered heterocyclyl is optionallysubstituted with one or more oxo. In another embodiment of Formula(III), R⁹, at each occurrence, is independently C₁-C₆ alkyl; whereineach R⁹ C₁-C₆ alkyl is optionally substituted with one or moresubstituents independently selected from the group consisting of R¹³ andF. In another embodiment of Formula (III), R⁹, at each occurrence, isindependently C₁-C₆ alkyl; wherein each R⁹ C₁-C₆ alkyl is unsubstituted.

In one embodiment of Formula (III), R¹⁰, at each occurrence, isindependently C₁-C₄ alkyl.

In one embodiment of Formula (III), R^(II), at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 memberedheterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl; whereineach R¹¹ C₁-C₆ alkyl and C₁-C₆ alkoxy is optionally substituted with oneor more substituents independently selected from the group consisting ofC₁-C₆ alkoxy, OH, oxo, CN, NO₂, F, Cl, Br and I; wherein each R¹¹ C₆-C₁₀membered aryl, C₃-C₁₁ cycloalkyl, 4-12 membered heterocyclyl, C₄-C₁₁cycloalkenyl, and 5-6 membered heteroaryl is optionally substituted withone or more substituents independently selected from the groupconsisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, F, Cl, Br and I. In anotherembodiment of Formula (III), R¹, at each occurrence, is independentlyC₁-C₆ alkyl; wherein each R¹¹ C₁-C₆ alkyl is optionally substituted withC₁-C₆ alkoxy.

In one embodiment of Formula (III), R¹², at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆alkoxy, C₆-C₁₀ membered aryl, C₃-C₁₁ cycloalkyl, 4-12 memberedheterocyclyl, C₄-C₁₁ cycloalkenyl, and 5-6 membered heteroaryl.

In one embodiment of Formula (III), R¹³, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹³ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of OH, oxo, CN, NO₂, F, Cl, Br and I;wherein each R¹³ C₆-C₁₀ membered aryl, 5-11 membered heteroaryl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, OH, oxo, CN, NO₂, F, Cl, Br and I. In anotherembodiment of Formula (III), R¹³, at each occurrence, is C₆-C₁₀ memberedaryl.

In one embodiment of Formula (III), R¹⁴, at each occurrence, isindependently selected from the group consisting of C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₆-C₁₀ membered aryl, 5-11 membered heteroaryl,C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkenyl, and 4-12 membered heterocyclyl;wherein each R¹⁴ C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkoxy, 5-6membered heteroaryl, 4-12 membered heterocyclyl, OH, oxo, CN, NO₂, F,Cl, Br and I.

In one embodiment of Formula (III),

-   -   R¹ is selected from the group consisting of 6-10 membered aryl,        5-11 membered heteroaryl, and 4-12 membered heterocyclyl;        wherein the R¹ 6-10 membered aryl, 5-11 membered heteroaryl, and        4-12 membered heterocyclyl are substituted with two or more        substituents independently selected from the group consisting of        R⁷, OR⁷, C(O)OR⁷, N(R⁷)₂, NH₂, CN, F, Cl, and Br;    -   R² is independently selected from the group consisting of R⁸ and        C(O)OR;    -   n is 0 or 1;    -   R³ is selected from the group consisting of C₁-C₆ alkyl, 6-10        membered aryl, 5-11 membered heteroaryl, C₃-C₁₁ cycloalkyl, and        4-12 membered heterocyclyl; wherein the R³ C₁-C₆ alkyl is        optionally substituted with one or more substituents        independently selected from the group consisting of phenyl, F,        and Cl; wherein the R³ 6-10 membered aryl, 5-11 membered        heteroaryl, C₃-C₁₁ cycloalkyl, and 4-12 membered heterocyclyl        are optionally substituted with one or more substituents        independently selected from the group consisting of R⁹, OR⁹,        C(O)R⁹, C(O)OR⁹, SO₂R⁹, NHR⁹, N(R⁹)₂, NH₂, C(O)OH, OH, oxo, CN,        NO₂, Cl, and Br;    -   R⁴ is selected from the group consisting of hydrogen and C₁-C₆        alkyl;    -   R⁷, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 5-11 membered heteroaryl, C₃-C₁₁        cycloalkyl, and 4-12 membered heterocyclyl; wherein each R⁷        C₁-C₆ alkyl is optionally substituted with one or more        substituents independently selected from the group consisting of        C₁-C₆ alkoxy, C₃-C₇ cycloalkyl, OH and F; wherein each R⁷ 5-11        membered heteroaryl, C₃-C₁₁ cycloalkyl and 4-12 membered        heterocyclyl is optionally substituted with one or more        substituents independently selected from the group consisting of        R¹¹, OR¹¹, NHR¹¹, and C(O)OR¹¹;    -   R⁸ is independently C₁-C₆ alkyl;    -   R⁹, at each occurrence, is independently selected from the group        consisting of C₁-C₆ alkyl, 5-11 membered heteroaryl, and 4-12        membered heterocyclyl; wherein each R⁹ C₁-C₆ alkyl, is        optionally substituted with one or more substituents        independently selected from the group consisting of R¹³ and F;        wherein each R⁹ 5-11 membered heteroaryl, and 4-12 membered        heterocyclyl is optionally substituted with one oxo;    -   R¹¹, at each occurrence, is independently C₁-C₆ alkyl; wherein        each R¹¹ C₁-C₆ alkyl is optionally substituted with one C₁-C₆        alkoxy; and    -   R¹³, at each occurrence, is independently C₆-C₁₀ membered aryl.

Exemplary compounds of Formula (III) include, but are not limited to:

-   1-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclopentyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-[5-(butan-2-yl)-2-methoxyphenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(3,4-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclobutane-1-carboxamide;    and    pharmaceutically acceptable salts thereof.

One embodiment pertains to:

-   1-(5-bromo-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(propan-2-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(2,5-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,5-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethoxy-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclobutyloxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-tert-butyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-tert-butyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-6-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2,3-dimethylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-6-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclobutyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2,3-dihydro-H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(difluoromethoxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-diethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(5-cyclobutyl-2-methoxyphenyl)cyclopropane-1-carboxamide;-   1-(5-cyclopropyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethoxy-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-tert-butyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxyquinolin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxyquinolin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(2,5-dimethylphenyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[1-(methylamino)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(2-ethoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(oxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(2-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-{[(2R)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-methylphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxycyclobutyl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-{[(2R)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[3-(dimethylamino)-6-(2-methylpropoxy)pyridin-2-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(dimethylamino)-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2S)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2S)-2-methoxypropoxy]-5-methylphenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2R)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(2R)-2-methoxypropoxy]-5-methylphenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-4-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(quinoline-5-sulfonyl)-1-[2-(trifluoromethoxy)phenyl]cyclobutane-1-carboxamide;-   1-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-(5-cyclopentyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-[5-(butan-2-yl)-2-methoxyphenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   1-{2-methoxy-5-[(oxolan-3-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-5-(trifluoromethoxy)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-5-(trifluoromethoxy)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclobutane-1-carboxamide;-   methyl    1-(4-methoxy-3-{1-[(quinoline-5-sulfonyl)carbamoyl]cyclopropyl}phenyl)cyclopropane-1-carboxylate;-   methyl    4-methoxy-3-{1-[(quinoline-5-sulfonyl)carbamoyl]cyclopropyl}benzoate;-   methyl    4-methoxy-3-{1-[(naphthalene-1-sulfonyl)carbamoyl]cyclopropyl}benzoate;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-bromo-2-methoxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2,3-dimethylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,6-dimethoxy-3-methylphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclobutyl-5-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclobutyl-5-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(hydroxymethyl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(methoxymethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2,3-dimethylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-chloro-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methoxy-2-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methoxy-2-propylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-6-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,5-dimethylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-4-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-3-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(4-cyclobutyl-2,6-dimethoxyphenyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-(5-ethyl-2-methoxyphenyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-(6-methoxy-2,3-dimethylphenyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   1-(2,5-dimethylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-6-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-[2-(methylamino)quinoline-5-sulfonyl]cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-methylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2,2,2-trifluoro-1-methoxyethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxyethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(3-methyloxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-(2-{[(2S)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methoxyquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(2-ethoxypropan-2-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-ethylphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxycyclobutyl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-methylphenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(difluoromethoxy)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-ethylphenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-{[(2S)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-ethoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-ethoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(difluoromethoxy)-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(1-ethoxy-2-methylpropan-2-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(1-ethoxy-2-methylpropan-2-yl)-2-methoxyphenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(dimethylamino)-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-methyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   N-(3-cyanobenzene-1-sulfonyl)-4-(3-fluorophenyl)oxane-4-carboxamide;-   N-(benzenesulfonyl)-1-(4-methoxyphenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-phenylcyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(4-chlorophenyl)cyclobutane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(2,3-dihydro-1H-indene-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   N-(4-chlorobenzene-1-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide;-   methyl    5-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}-4-methoxythiophene-3-carboxylate;-   1-(2,4-dichlorophenyl)-N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[2-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[4-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[3-(trifluoromethyl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[4-(2-oxopyrrolidin-1-yl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[5-(1,2-oxazol-5-yl)thiophene-2-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[4-(pyrrolidine-1-sulfonyl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)-N-methylcyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-{4-[(propan-2-yl)oxy]benzene-1-sulfonyl}cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[6-(morpholin-4-yl)pyridine-3-sulfonyl]cyclopropane-1-carboxamide;-   benzyl    4-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;-   N-(2-chlorobenzene-1-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(4-methoxybenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(3,4-dimethoxybenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(3-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(naphthalene-2-sulfonyl)cyclopropane-1-carboxamide;-   N-(cyclopropanesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(4-methylphenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(2-fluorophenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(4-fluorophenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(2-chlorophenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-1-(3,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2-fluorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(1,1-dioxo-1λ⁶-thiolane-3-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(4-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-cyano-5-fluorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   N-(2-chloro-5-nitrobenzene-1-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide;-   1-(3-chlorophenyl)-N-(6-ethoxy-1,3-benzothiazole-2-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-chlorophenyl)-N-(5-hydroxynaphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-chlorophenyl)-N-[5-(dimethylamino)naphthalene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(pyridine-3-sulfonyl)cyclopropane-1-carboxamide;-   N-(6-chloropyridine-3-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   N-(benzenesulfonyl)-2,2-dimethyl-1-phenylcyclopropane-1-carboxamide;-   methyl    5-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}furan-2-carboxylate;-   N-(5-bromothiophene-2-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[3-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   methyl    2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoate;-   methyl    4-chloro-2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoate;-   2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoic    acid;-   4-chloro-2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoic    acid;-   benzyl    4-{[1-(4-methylphenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;-   benzyl    4-{[1-(3,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;-   N-(benzenesulfonyl)-1-(3-bromophenyl)cyclopropane-1-carboxamide;-   1-(3-chlorophenyl)-N-[2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]cyclopropane-1-carboxamide;-   1-(3-chlorophenyl)-N-[4-(1H-pyrazol-1-yl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;-   1-(3-chlorophenyl)-N-(3,4-dimethylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-chlorophenyl)-N-(2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(piperidine-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1-acetylpiperidine-4-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-[1-(3-phenylpropanoyl)piperidine-4-sulfonyl]cyclopropane-1-carboxamide;-   tert-butyl    4-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;-   4-(3-methoxyphenyl)-N-(2-methylbenzene-1-sulfonyl)oxane-4-carboxamide;-   N-(2-methylbenzene-1-sulfonyl)-4-(3-methylphenyl)oxane-4-carboxamide;-   1-(3-chlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopentane-1-carboxamide;-   1-(3-chlorophenyl)-N-(5-methylpyridine-2-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxyphenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2H-1,3-benzodioxol-5-yl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-chlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;-   tert-butyl    4-(4-fluorophenyl)-4-[(naphthalene-1-sulfonyl)carbamoyl]piperidine-1-carboxylate;-   1-(3,4-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopentane-1-carboxamide;-   1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-bromophenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-bromophenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   4-(5-methoxy-2-methylphenyl)-1-methyl-N-(quinoline-5-sulfonyl)piperidine-4-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-(5-cyano-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyano-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-6-methylphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(3,5-dichloro-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(trifluoromethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(2,2,2-trifluoroethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(propane-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(3-chloropropane-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;-   1-(3-chlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dichlorophenyl)-N-(propane-2-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-methylphenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   1-(4-fluorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   1-(2-chlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   1-(4-chlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   1-(3,4-dichlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;-   N-(pentane-3-sulfonyl)-1-phenylcyclopropane-1-carboxamide;-   4-(3-methoxyphenyl)-N-(propane-1-sulfonyl)oxane-4-carboxamide;-   4-(3-methylphenyl)-N-(propane-1-sulfonyl)oxane-4-carboxamide;-   1-(3,4-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclobutane-1-carboxamide;-   1-[2-methoxy-6-(1-methyl-1H-pyrazol-4-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-6-methylpyridin-2-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-6-methylpyridin-2-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-methoxy-6-methylpyridin-2-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,5-dimethylphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(3-methoxyoxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(3-²H)oxetan-3-yl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   N-(1H-indazole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-(2-ethyl-6-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethyl-6-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-[2-(dimethylamino)quinoline-5-sulfonyl]-1-(2-ethoxy-5-methylphenyl)cyclopropane-1-carboxamide;-   1-{5-bromo-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide    1-{5-bromo-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-chloro-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide-   1-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(propan-2-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(propan-2-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide.    1-[2-cyclopropyl-5-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-methoxy-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(propan-2-yl)oxy]-5-(pyrrolidin-1-yl)pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-methylquinoline-5-sulfonyl)-1-{2-[(propan-2-yl)xy]-5-(pyrrolidin-1-yl)pyridin-3-yl}cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{2-[(propan-2-yl)oxy]-5-(pyrrolidin-1-yl)pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}cyclopropane-1-carboxamide;-   1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-ethoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-cyclobutyl-2-ethoxypyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-ethylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethoxy-5-ethylpyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-[1-(methoxymethyl)cyclopropyl]-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dimethoxypyrimidin-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   N-(naphthalene-1-sulfonyl)-1-{2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-{2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-chloro-2-methoxypyridin-4-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide-   1-(5-chloro-2-methoxypyridin-4-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(morpholin-4-yl)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide-   1-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-methylpyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-methoxy-5-methylpyridin-4-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-cyclopropyl-5-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-ethyl-5-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-ethyl-5-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[6-(dimethylamino)-2-methoxypyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-ethylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-ethylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-4-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-4-methylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(2-methylquinoline-5-sulfonyl)-1-[2-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-methyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-5-methylpyridin-2-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[5-methoxy-2-(2-methoxyethoxy)pyridin-3-yl]cyclopropane-1-carboxamide;-   1-[5-methoxy-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methoxyethoxy)pyridin-4-yl]cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxyethoxy)pyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-ethylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-ethylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(dimethylamino)-5-ethylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methoxyethoxy)-5-methylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-(dimethylamino)-6-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-(2-methoxyethoxy)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-[2-(2-methoxyethoxy)-5-methylpyridin-3-yl]cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-ethyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-chloro-2-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   N-(1H-indole-4-sulfonyl)-1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;-   1-(3-cyclopropyl-5-methylpyridin-2-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-5-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(4-ethylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-fluoro-5-methylpyridin-4-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2-methylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-methoxy-5-(2-methoxyethoxy)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dimethoxypyrimidin-5-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{2-chloro-5-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(2,2-difluoroethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-2-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2-fluoro-5-methylpyridin-4-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-methoxy-4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(2,2-difluoroethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-(difluoromethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(2,4-dimethoxypyrimidin-5-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(morpholin-4-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-methyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(6-amino-2-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclobutyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-ethyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-(5-chloro-2-fluoropyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-{5-(hydroxymethyl)-2-[(propan-2-yl)xy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;-   1-[5-cyclopropyl-2-(4-methylpiperazin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;    and pharmaceutically acceptable salts thereof.

Various embodiments of A¹, R¹, R², R³, R⁴, and n have been discussedabove. These embodiments can be combined to form various embodiments ofthe invention. All embodiments of present compounds, formed by combiningthe substituent embodiments discussed above are within the scope ofApplicant's invention.

Compounds of the invention were named using Name 2016.1.1 (File VersionN30E41, Build 86668, 25 May, 2016) or Name 2017.2.1 (File VersionN40E41, Build 96719, 6 Sep. 2017) naming algorithm by Advanced ChemicalDevelopment, Inc., or Struct=Name naming algorithm as part of CHEMDRAW®ULTRA v. 12.0.2.1076 or Professional Version 15.0.0.106.

Compounds of the invention may exist as stereoisomers wherein asymmetricor chiral centers are present. These stereoisomers are “R” or “S”depending on the configuration of substituents around the chiral carbonatom. The terms “R” and “S” used herein are configurations as defined inIUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry,in Pure Appl. Chem., 1976, 45: 13-30. The invention contemplates variousstereoisomers and mixtures thereof and these are specifically includedwithin the scope of this invention. Stereoisomers include enantiomersand diastereomers, and mixtures of enantiomers or diastereomers.Individual stereoisomers of compounds of the invention may be preparedsynthetically from commercially available starting materials whichcontain asymmetric or chiral centers or by preparation of racemicmixtures followed by methods of resolution well-known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and optional liberation of theoptically pure product from the auxiliary as described in Fumiss,Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical OrganicChemistry”, 5th edition (1989), Longman Scientific & Technical, EssexCM20 2JE, England, or (2) direct separation of the mixture of opticalenantiomers on chiral chromatographic columns or (3) fractionalrecrystallization methods.

Compounds of the invention may exist as cis or trans isomers, whereinsubstituents on a ring may attached in such a manner that they are onthe same side of the ring (cis) relative to each other, or on oppositesides of the ring relative to each other (trans). For example,cyclobutane may be present in the cis or trans configuration, and may bepresent as a single isomer or a mixture of the cis and trans isomers.Individual cis or trans isomers of compounds of the invention may beprepared synthetically from commercially available starting materialsusing selective organic transformations, or prepared in single isomericform by purification of mixtures of the cis and trans isomers. Suchmethods are well-known to those of ordinary skill in the art, and mayinclude separation of isomers by recrystallization or chromatography.

It should be understood that the compounds of the invention may possesstautomeric forms, as well as geometric isomers, and that these alsoconstitute an aspect of the invention.

The present disclosure includes all pharmaceutically acceptableisotopically-labelled compounds of Formula (I), II, and III wherein oneor more atoms are replaced by atoms having the same atomic number, butan atomic mass or mass number different from the atomic mass or massnumber which predominates in nature. Examples of isotopes suitable forinclusion in the compounds of the disclosure include isotopes ofhydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine,such as ³⁶Cl, fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I,nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O,phosphorus, such as ³²P, and sulphur, such as ³⁵S. Certainisotopically-labelled compounds of Formula (I), II, and III for example,those incorporating a radioactive isotope, are useful in drug and/orsubstrate tissue distribution studies. The radioactive isotopes tritium,i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for thispurpose in view of their ease of incorporation and ready means ofdetection. Substitution with heavier isotopes such as deuterium, i.e.²H, may afford certain therapeutic advantages resulting from greatermetabolic stability, for example, increased in vivo half-life or reduceddosage requirements, and hence may be preferred in some circumstances.Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof Formula (I), II, and III may generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the accompanying Examples using an appropriateisotopically-labeled reagents in place of the non-labeled reagentpreviously employed.

Thus, the formula drawings within this specification can represent onlyone of the possible tautomeric, geometric, or stereoisomeric forms. Itis to be understood that the invention encompasses any tautomeric,geometric, or stereoisomeric form, and mixtures thereof, and is not tobe limited merely to any one tautomeric, geometric, or stereoisomericform utilized within the formula drawings.

Compounds of Formula (I), (II), and (III) may be used in the form ofpharmaceutically acceptable salts. The phrase “pharmaceuticallyacceptable salt” means those salts which are, within the scope of soundmedical judgement, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse and the like and are commensurate with a reasonablebenefit/risk ratio.

Compounds of Formula (I), (II), and (III) may contain either a basic oran acidic functionality, or both, and can be converted to apharmaceutically acceptable salt, when desired, by using a suitable acidor base. The salts may be prepared in situ during the final isolationand purification of the compounds of the invention.

The term “pharmaceutically acceptable prodrug” or “prodrug”, as usedherein, refers to derivatives of the compounds of the invention whichhave cleavable groups. Such derivatives become, by solvolysis or underphysiological conditions, the compounds of the invention which arepharmaceutically active in vivo. Prodrugs of the compounds of theinvention are, within the scope of sound medical judgement, suitable foruse in contact with the tissues of humans and lower animals withoutundue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The invention contemplates compounds of Formula (I), (II), and (III)formed by synthetic means or formed by in vivo biotransformation of aprodrug.

Compounds described herein may exist in unsolvated as well as solvatedforms, including hydrated forms, such as hemi-hydrates. In general, thesolvated forms, with pharmaceutically acceptable solvents such as waterand ethanol among others are equivalent to the unsolvated forms for thepurposes of the invention.

Pharmaceutical Compositions

When employed as a pharmaceutical, a compound of the invention istypically administered in the form of a pharmaceutical composition thatcomprise a therapeutically effective amount of a compound of Formula(I), (II), (III), or a pharmaceutically acceptable salt thereof,together with a pharmaceutically acceptable carrier. The phrase“pharmaceutical composition” refers to a composition suitable foradministration in medical or veterinary use. The term “pharmaceuticallyacceptable carrier” as used herein, means a non-toxic, inert solid,semi-solid or liquid filler, diluent, encapsulating material orformulation auxiliary of any type.

Methods of Use

The compounds and compositions using any amount and any route ofadministration may be administered to a subject for the treatment orprevention of cystic fibrosis, pancreatic insufficiency, Sjögren'sSyndrome (SS), chronic obstructive lung disease (COLD), or chronicobstructive airway disease (COAD).

The term “administering” refers to the method of contacting a compoundwith a subject.

Compounds of the invention are useful as modulators of CFTR. Thus, thecompounds and compositions are particularly useful for treating orlessening the severity or progression of a disease, disorder, or acondition where hyperactivity or inactivity of CFTR is involved.Accordingly, the invention provides a method for treating cysticfibrosis in a subject, wherein the method comprises the step ofadministering to said subject a therapeutically effective amount of acompound of Formula (I), (II), or (III) or a preferred embodimentthereof as set forth above, with or without a pharmaceuticallyacceptable carrier. Particularly, the method is for the treatment orprevention of cystic fibrosis. In a more particular embodiment, thecystic fibrosis is caused by a Class I, II, III, IV, V, and/or VImutation.

In another embodiment, the present invention provides compounds of theinvention, or pharmaceutical compositions comprising a compound of theinvention for use in medicine. In a particular embodiment, the presentinvention provides compounds of the invention, or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising acompound of the invention, for use in medicine. In a particularembodiment, the present invention provides compounds of the invention orpharmaceutical compositions comprising a compound of the invention, foruse in the treatment of cystic fibrosis. In a more particularembodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V,and/or VI mutation.

One embodiment is directed to the use of a compound according to Formula(I), (II) or (III), or a pharmaceutically acceptable salt thereof, inthe preparation of a medicament. The medicament optionally can compriseone or more additional therapeutic agents. In some embodiments, themedicament is for use in the treatment of cystic fibrosis. In a moreparticular embodiment, the cystic fibrosis is caused by a Class I, II,III, IV, V, and/or VI mutation.

This invention also is directed to the use of a compound according toFormula (I), (II) or (III), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment of cysticfibrosis. The medicament optionally can comprise one or more additionaltherapeutic agents. In a particular embodiment, the invention isdirected to the use of a compound according to Formula (I), (II) or(III), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for the treatment of cystic fibrosis. In a moreparticular embodiment, the cystic fibrosis is caused by a Class I, II,III, IV, V, and/or VI mutation.

In one embodiment, the present invention provides pharmaceuticalcompositions comprising a compound of the invention, or apharmaceutically acceptable salt thereof, and one or more additionaltherapeutic agents. In another embodiment, the present inventionprovides pharmaceutical compositions comprising a compound of theinvention, or a pharmaceutically acceptable salt thereof, and one ormore additional therapeutic agents wherein the additional therapeuticagents are selected from the group consisting of CFTR modulators andCFTR amplifiers. In another embodiment, the present invention providespharmaceutical compositions comprising a compound of the invention, or apharmaceutically acceptable salt thereof, and one or more additionaltherapeutic agents wherein the additional therapeutic agents are CFTRmodulators.

The present compounds or pharmaceutically acceptable salts thereof maybe administered as the sole active agent or it may be co-administeredwith other therapeutic agents, including other compounds or apharmaceutically acceptable salt thereof that demonstrate the same or asimilar therapeutic activity and that are determined to be safe andefficacious for such combined administration. The present compounds maybe co-administered to a subject. The term “co-administered” means theadministration of two or more different therapeutic agents to a subjectin a single pharmaceutical composition or in separate pharmaceuticalcompositions. Thus co-administration involves administration at the sametime of a single pharmaceutical composition comprising two or moretherapeutic agents or administration of two or more differentcompositions to the same subject at the same or different times.

The compounds of the invention or pharmaceutically acceptable saltsthereof may be co-administered with a therapeutically effective amountof one or more additional therapeutic agents to treat a CFTR mediateddisease, where examples of the therapeutic agents include, but are notlimited to antibiotics (for example, aminoglycosides, colistin,aztreonam, ciprofloxacin, and azithromycin), expectorants (for example,hypertonic saline, acetylcysteine, dornase alfa, and denufosol),pancreatic enzyme supplements (for example, pancreatin, andpancrelipase), epithelial sodium channel blocker (ENaC) inhibitors, CFTRmodulators (for example, CFTR potentiators, CFTR correctors), and CFTRamplifiers.

In one embodiment, the compounds of the invention or pharmaceuticallyacceptable salts thereof may be co-administered with one or two CFTRmodulators and one CFTR amplifier. In one embodiment, the compounds ofthe invention or pharmaceutically acceptable salts thereof may beco-administered with one potentiator, one or more correctors, and oneCFTR amplifier. In one embodiment, the compounds of the invention orpharmaceutically acceptable salts thereof may be co-administered withone or more CFTR modulators. In one embodiment, the compounds of theinvention or pharmaceutically acceptable salts thereof may beco-administered with one CFTR modulator. In one embodiment, thecompounds of the invention or pharmaceutically acceptable salts thereofmay be co-administered with two CFTR modulators. In one embodiment, thecompounds of the invention or pharmaceutically acceptable salts thereofmay be co-administered with three CFTR modulators. In one embodiment,the compounds of the invention or pharmaceutically acceptable saltsthereof may be co-administered with one potentiator and one or morecorrectors. In one embodiment, the compounds of the invention orpharmaceutically acceptable salts thereof may be co-administered withone potentiator and two correctors. In one embodiment, the compounds ofthe invention or pharmaceutically acceptable salts thereof may beco-administered with one potentiator. In one embodiment, the compoundsof the invention or pharmaceutically acceptable salts thereof may beco-administered with one or more correctors. In one embodiment, thecompounds of the invention or pharmaceutically acceptable salts thereofmay be co-administered with one corrector. In one embodiment, thecompounds of the invention or pharmaceutically acceptable salts thereofmay be co-administered two correctors. In one embodiment, the compoundsof the invention or pharmaceutically acceptable salts thereof may beco-administered with one or more correctors, and one amplifier. In oneembodiment, the compounds of the invention or pharmaceuticallyacceptable salts thereof may be co-administered with one corrector, andone amplifier. In one embodiment, the compounds of the invention orpharmaceutically acceptable salts thereof may be co-administered withtwo correctors, and one amplifier. In one embodiment, the compounds ofthe invention or pharmaceutically acceptable salts thereof may beco-administered with one corrector. In one embodiment, the compounds ofthe invention or pharmaceutically acceptable salts thereof may beco-administered with two correctors.

Examples of CFTR potentiators include, but are not limited to, Ivacaftor(VX-770), GLPG2451, GLPG1837, CTP-656, NVS-QBW251, FD1860293, PTI-808,N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide,and3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide.Examples of potentiators are also disclosed in publications:WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421,WO2008147952, WO2011072241, WO2011113894, WO2013038373, WO2013038378,WO2013038381, WO2013038386, WO2013038390, WO2014/180562, WO2015018823,WO2016193812 and WO2017208115.

In one embodiment, the potentiator can be selected from the groupconsisting of

Ivacaftor (VX-770,N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide);

-   -   GLPG2451;    -   GLPG1837,    -   CTP-656;    -   NVS-QBW251;    -   FD1860293;    -   PTI-808;

-   2-(2-fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide;

-   2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

-   2-(1-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

-   5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

-   2-(2-hydroxy-2-methylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

-   2-(1-(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

-   2-(3-hydroxy-2,2-dimethylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-1H-pyrazole-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-isopropyl-1H-pyrazole-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide;

-   5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-ethyl-1H-pyrazole-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide;

-   2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-1H-pyrazole-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;

-   4-bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-1H-pyrazole-3-carboxamide;

-   2-(2-hydroxy-3,3-dimethylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;

-   2-[(2-hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

-   5-(2-methoxy-ethoxy)-1H-pyrazole-3-carboxylic acid    (3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3-methoxypropyl)-1H-pyrazole-3-carboxamide;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethoxyethyl)-1H-pyrazole-3-carboxamide;

-   2-[[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

-   2-[[(2R)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

-   2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

-   [5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl    dihydrogen phosphate;

-   [3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl    dihydrogen phosphate;

-   N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,4-dioxan-2-yl)-1H-pyrazole-3-carboxamide;

-   5,5,7,7-tetramethyl-2-[[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl]amino]-4H-thieno[2,3-c]pyran-3-carboxamide;

-   2-[[(2S)-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;

-   3-amino-N-(2-hydroxy-2-methylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

-   3-amino-N-[(4-hydroxy-1-methylpiperidin-4-yl)methyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

-   3-amino-N-(3-hydroxy-2,2-dimethylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

-   3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]pyridine-2-carboxamide;

-   3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]pyridine-2-carboxamide;

-   3-amino-5-[(3-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide;

-   3-amino-N-[2-(cyclopropylamino)-2-oxoethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

-   (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)    (azetidin-1-yl)methanone;

-   (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)    [3-(hydroxymethyl)azetidin-1-yl]methanone;

-   (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-fluoroazetidin-1-yl)methanone;

-   3-amino-N-[(2R)-2-hydroxy-3-methoxypropyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;

-   (3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone;

-   (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone;

-   rac-3-amino-N-[(3R,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

-   3-amino-5-[(4,4-difluoropiperidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;

-   (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)    [3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

-   3-amino-N-(2-hydroxy-4-methylpentyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

-   (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone;

-   3-amino-N-(3,3,3-trifluoro-2-hydroxypropyl)-5-{[4-(trifluoromethyl)piperidin-1-yl]sulfonyl}pyridine-2-carboxamide;

-   3-amino-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;

-   3-amino-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;

-   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2S)-2-hydroxypropyl]pyridine-2-carboxamide;

-   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2R)-2-hydroxy-3-methoxypropyl]pyridine-2-carboxamide;

-   3-amino-N-[2-oxo-2-(propan-2-ylamino)ethyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;

-   (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)    [3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

-   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3R)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;

-   (3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)    [3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

-   3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;

-   3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;

-   3-amino-N-[2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;

-   3-amino-N-(3-tert-butoxy-2-hydroxypropyl)-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;

-   [3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;

-   {3-amino-5-[(3-fluorophenyl)    sulfonyl]pyridin-2-yl}[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;    and

-   3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide.

Non-limiting examples of correctors include Lumacaftor (VX-809),1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide(VX-661), VX-983, GLPG2222, GLPG2665, GLPG2737, GLPG2851, GLPG3221,PTI-801, VX-152, VX-440, VX-659, VX-445, FDL169, FDL304, FD2052160, andFD2035659. Examples of correctors are also disclosed in U.S. applicationSer. Nos. 14/925,649, 14/926,727, 15/205,512, 15/496,094, 15/287,922,15/287,911, 15/723,896 and 15/726,075.

In one embodiment, the corrector(s) can be selected from the groupconsisting of

Lumacaftor (VX-809);

-   1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide    (VX-661);

VX-983;

GLPG2665;

GLPG2737;

GLPG3221;

PTI-801;

VX-152;

VX-440;

VX-659;

VX-445

FDL169

FDL304;

FD2052160;

FD2035659;

-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcyclopentanecarboxylic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxypropyl]benzamide;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic    acid;-   4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic    acid;-   rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic    acid;-   3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic    acid;-   3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic    acid;-   4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic    acid;-   4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1l-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1l-yl]-N-[2-(morpholin-4-yl)ethanesulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-N-[2-(dimethylamino)ethane    sulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(1′-methyl[4,4′-bipiperidin]-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-N-(methanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1l-yl]-N-(oxolane-3-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-N-(dimethylsulfamoyl)-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-N-(morpholine-4-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-N-(morpholine-4-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1l-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;-   3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic    acid;-   3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic    acid;-   5-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]pyrazine-2-carboxylic    acid;-   6-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic    acid;-   trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   6-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic    acid;-   trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   ethyl    trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate;-   cis-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-J][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   1-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclopropane-1-carboxylic    acid;-   trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-J][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   4-{(2R,4R)-4-[2-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-2-methylpropanamido]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic    acid;-   4-[(2R,4R)-4-{[1-(3,4-dichlorophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic    acid;-   4-[(2R,4R)-4-{[1-(4-bromophenyl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic    acid;-   4-[(2R,4R)-7-methoxy-4-({1-[4-(trifluoromethyl)phenyl]cyclopropane-1-carbonyl}amino)-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic    acid;-   4-[(2R,4R)-7-methoxy-4-{[1-(4-methylphenyl)cyclopropane-1-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic    acid;-   4-{(2R,4R)-4-[(1,5-dimethyl-2,3-dihydro-1H-indene-carbonyl)amino]-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl}benzoic    acid;-   3-[(2R,4R)-4-{[(1S)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic    acid;-   4-[(2R,4R)-4-{[(1S)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]benzoic    acid;-   trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid;-   trans-4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid; and-   4-[(2R,4R)-4-{[1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)cyclopropane-1-carbonyl]amino}-7-(difluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic    acid.

In one embodiment, the additional therapeutic agent is a CFTR amplifier.CFTR amplifiers enhance the effect of known CFTR modulators, such aspotentiators and correctors. Examples of CFTR amplifiers include PTI130and PTI-428. Examples of amplifiers are also disclosed in InternationalPatent Publication Nos.: WO2015138909 and WO2015138934.

In one embodiment, the additional therapeutic agent is a CFTRstabilizer. CFTR stabilizers enhance the stability of corrected CFTRthat has been treated with a corrector, corrector/potentiator or otherCFTR modulator combination(s). An example of a CFTR stabilizer iscavosonstat (N91115). Examples of stabilizers are also disclosed inInternational Patent Publication No.: WO2012048181.

In one embodiment, the additional therapeutic agent is an agent thatreduces the activity of the epithelial sodium channel blocker (ENaC)either directly by blocking the channel or indirectly by modulation ofproteases that lead to an increase in ENaC activity (e.g., serineproteases, channel-activating proteases). Exemplary of such agentsinclude camostat (a trypsin-like protease inhibitor), QAU145, 552-02,GS-9411, INO-4995, Aerolytic, amiloride, and VX-371. Additional agentsthat reduce the activity of the epithelial sodium channel blocker (ENaC)can be found, for example, in International Patent Publication Nos.:WO2009074575 and WO2013043720; and U.S. Pat. No. 8,999,976.

In one embodiment, the ENaC inhibitor is VX-371.

In one embodiment, the ENaC inhibitor is SPX-101 (S18).

This invention also is directed to kits that comprise one or morecompounds and/or salts of the invention, and, optionally, one or moreadditional therapeutic agents.

This invention also is directed to methods of use of the compounds,salts, compositions, and/or kits of the invention to, for example,modulate the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)protein, and treat a disease treatable by modulating the Cystic FibrosisTransmembrane Conductance Regulator (CFTR) protein (including cysticfibrosis, Sjögren's syndrome, pancreatic insufficiency, chronicobstructive lung disease, and chronic obstructive airway disease).

General Synthesis

The compounds of the present disclosure can be better understood inconnection with the following synthetic schemes and methods whichillustrate a means by which the compounds can be prepared.

The compounds of this disclosure can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1-4. In Schemes 1-4, the variables A¹, R¹, R²,R³, R⁴, and n are is as described in the Summary, or they represent amoiety that can be converted to one of said groups using chemicaltransformations known to one of skill in the art.

Schemes

Scheme 1 describes the synthesis of compounds of formula (7) fromcompounds of formula (1). Compounds of formula (1), wherein R² and n areas described herein, can be treated with a zinc slurry containing amixture of indium(III) chloride, zinc and bromine to provide organozinccompounds of formula (2). The reaction is typically performed undernitrogen at ambient temperature in a solvent such as, but not limited totetrahydrofuran, before increasing to an elevated temperature after theaddition.

Compounds of formula (4) can be prepared by reacting compounds offormula (3) wherein R¹ is as described herein and X is I, Br, Cl ortriflate, with organozinc compounds of formula (2) under Negishicoupling conditions known to those skilled in the art and widelyavailable in the literature. The reaction typically requires the use ofa palladium or nickel catalyst, and may require the use of a ligand.Examples of catalysts include, but are not limited to,dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl), tetrakis(triphenylphosphine)nickel(0),tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, tris(dibenzylideneacetone)dipalladium(0), andpalladium(II) acetate. Examples of ligands include, but are not limitedto, triphenylphosphine, 1,2-bis(diphenylphosphino)ethane (dppe),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), Chiraphos, and1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene. The reactionmay be conducted in a solvent such as, but not limited to, water,dioxane, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide,1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,tetrahydrofuran and the like, or mixtures thereof. The reaction may beconducted at ambient or elevated temperatures, and optionally in amicrowave oven.

Esters of formula (4) can be hydrolyzed in an aqueous hydroxide solutionto provide compounds of formula (5). The reaction is typically performedin a solvent such as, but not limited to, methanol, tetrahydrofuran, ormixtures thereof, and may be performed at ambient temperature or anelevated temperature.

Carboxylic acids of formula (5) can be coupled with sulfonamides offormula (6), wherein R³ is as described herein, to provide compounds offormula (7), which are representative of compounds of Formula (I).Examples of conditions known to generate compounds of formula (7) from amixture of a carboxylic acid and a sulfonamide include, but are notlimited to, adding a coupling reagent such as, but not limited to,N-(3-dimethylaminopropyl)-N-ethylcarbodiimide or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI) or thecorresponding hydrochloride salt, 1,3-dicyclohexylcarbodiimide (DCC),bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide or2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate or1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (HBTU), and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®).The coupling reagents may be added as a solid, a solution, or as thereagent bound to a solid support resin. In addition to the couplingreagents, auxiliary-coupling reagents may facilitate the couplingreaction. Auxiliary coupling reagents that are often used in thecoupling reactions include but are not limited to4-(dimethylamino)pyridine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT)and 1-hydroxybenzotriazole (HOBT). The reaction may be carried outoptionally in the presence of a base such as, but not limited to,triethylamine, N,N-diisopropylethylamine or pyridine. The couplingreaction may be carried out in solvents such as, but not limited to,tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, and ethyl acetate. The reactions may becarried out at ambient temperature or an elevated temperature. Theheating can be accomplished either conventionally or with microwaveirradiation.

As shown in Scheme 2, compounds of formula (12) can be prepared fromcompounds of formula (8). Compounds of formula (8), wherein R¹ is asdescribed herein, can be treated with an aqueous solution of sodiumcyanide to provide compounds of formula (9). The reaction is typicallyperformed at an elevated temperature in a solvent such as, but notlimited to, ethanol.

Compounds of formula (10) can be prepared by reacting compounds offormula (9) with a strong base such as, but not limited to sodiumhydride, followed by 1,2-dibromoethane. The reaction is typicallyperformed at ambient temperature in a solvent such as, but not limitedto, N,N-dimethylformamide.

Compounds of formula (10) can be treated with a strong acid or a strongbase such as sodium or lithium hydroxide to provide compounds of formula(11). The reaction is typically performed at an elevated temperature ina solvent such as, but not limited to, ethanol.

Carboxylic acids of formula (11) can be coupled with sulfonamides offormula (6) as described in Scheme 1, wherein R³ is as described herein,to provide compounds of formula (12), which are representative ofcompounds of Formula (I).

Scheme 3 describes the synthesis of compounds of formula (18) fromcompounds of formula (13). Compounds of formula (13), wherein R¹ and A¹are as described herein, can be treated with N-bromosuccinimide toprovide compounds of formula (14). The reaction is typically performedat ambient temperature in a solvent such as, but not limited to,dichloromethane.

Carboxylic acids of formula (14) can be coupled with sulfonamides offormula (6) as described in Scheme 1, wherein R³ is as described herein,to provide compounds of formula (15).

Compounds of formula (18), which are representative of compounds ofFormula (I), can be prepared by reacting compounds of formula (15) withorganozinc compounds of formula (16), wherein R² is as described herein,under Negishi coupling conditions known to those skilled in the art andwidely available in the literature. The reaction typically requires theuse of a palladium or nickel catalyst, and may require the use of aligand. Examples of catalysts include, but are not limited to,dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl), tetrakis(triphenylphosphine)nickel(0),tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, tris(dibenzylideneacetone)dipalladium(0), andpalladium(II) acetate. Examples of ligands include, but are not limitedto, triphenylphosphine, 1,2-bis(diphenylphosphino)ethane (dppe),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), Chiraphos, and1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene. The reactionmay be conducted in a solvent such as, but not limited to, water,dioxane, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide,1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,tetrahydrofuran and the like, or mixtures thereof. The reaction may beconducted at ambient or elevated temperatures, and optionally in amicrowave oven.

Alternatively, compounds of formula (18) can be prepared by reactingcompounds of formula (15) with boronic acid compounds of formula (17),wherein R² is as described herein (or the boronic ester equivalents),under Suzuki coupling conditions known to those skilled in the art andwidely available in the literature. The reaction typically requires theuse of a base and a catalyst. Examples of bases include, but are notlimited to, potassium carbonate, potassium t-butoxide, sodium carbonate,cesium carbonate, and cesium fluoride. Examples of catalysts include,but are not limited to, tetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, bis(triphenylphosphine)palladium(II) dichloride, andtris(dibenzylideneacetone)dipalladium(0). The reaction may be conductedin a solvent such as, but not limited to, water, dioxane,1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,tetrahydrofuran and the like or mixtures thereof. The reaction may beconducted at ambient or elevated temperatures, and optionally in amicrowave oven.

As described in Scheme 4, compounds of formula (19), wherein A¹ and R¹are as described herein, and R is an alkyl group, can be treated withbenzyltrimethylammonium tribromide to provide compounds of formula (20).The reaction is typically performed at ambient temperature in a solventsuch as, but not limited to, tetrahydrofuran, water, or mixturesthereof.

Compounds of formula (21) can be prepared by reacting compounds offormula (20) with organozinc compounds of formula (16), wherein R² is asdescribed herein, under Negishi coupling conditions known to thoseskilled in the art and widely available in the literature. The reactiontypically requires the use of a palladium or nickel catalyst, and mayrequire the use of a ligand. Examples of catalysts include, but are notlimited to,dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)(PEPPSI-IPentCl), tetrakis(triphenylphosphine)nickel(0),tetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) dichloride,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, tris(dibenzylideneacetone)dipalladium(0), andpalladium(II) acetate. Examples of ligands include, but are not limitedto, triphenylphosphine, 1,2-bis(diphenylphosphino)ethane (dppe),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), Chiraphos, and1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene. The reactionmay be conducted in a solvent such as, but not limited to, water,dioxane, 1-methyl-2-pyrrolidinone, N,N-dimethylacetamide,1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,tetrahydrofuran and the like, or mixtures thereof. The reaction may beconducted at ambient or elevated temperatures, and optionally in amicrowave oven.

Alternatively, compounds of formula (21) can be prepared by reactingcompounds of formula (20) with boronic acid compounds of formula (17),wherein R² is as described herein (or the boronic ester equivalents),under Suzuki coupling conditions known to those skilled in the art andwidely available in the literature. The reaction typically requires theuse of a base and a catalyst. Examples of bases include, but are notlimited to, potassium carbonate, potassium t-butoxide, sodium carbonate,cesium carbonate, and cesium fluoride. Examples of catalysts include,but are not limited to, tetrakis(triphenylphosphine)palladium(0),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, bis(triphenylphosphine)palladium(II) dichloride, andtris(dibenzylideneacetone)dipalladium(0). The reaction may be conductedin a solvent such as, but not limited to, water, dioxane,1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,tetrahydrofuran and the like or mixtures thereof. The reaction may beconducted at ambient or elevated temperatures, and optionally in amicrowave oven.

Esters of formula (21) can be hydrolyzed in an aqueous hydroxidesolution to provide compounds of formula (22). The reaction is typicallyperformed in a solvent such as, but not limited to, methanol,tetrahydrofuran, or mixtures thereof, and may be performed at ambienttemperature or an elevated temperature.

Carboxylic acids of formula (22) can be coupled with sulfonamides offormula (6) as described in Scheme 1, wherein R³ is as described herein,to provide compounds of formula (18), which are representative ofcompounds of Formula (I).

Chemical Synthetic Procedures

List of abbreviations used in the examples section: min for minute; DBUfor 1,8-diazabicyclo[5.4.0]undec-7-ene; DCI for desorption chemicalionization; DMSO for dimethyl sulfoxide; EDCI for1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; ESI forelectrospray ionization; HATU for1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate; HPLC for high performance liquidchromatography; MS for mass spectrometry; NMR for nuclear magneticresonance; wt for weight, and UPLC for ultra performance liquidchromatography.

The compounds of the invention can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e. reaction temperatures, times, mole ratios of reactants,solvents, pressures, etc.) were given, other process conditions can alsobe used unless otherwise stated. Optimum reaction conditions may varywith the particular reactants or solvent used, but such conditions canbe determined by one skilled in the art by routine optimizationprocedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art (Protective Groups in Organic Synthesis Third Edition; Greene, TW and Wuts, P G M, Eds.; Wiley-Interscience: New York, 1991).

The following methods are presented with details as to the preparationof a compound of the invention as defined hereinabove and thecomparative examples. A compound of the invention may be prepared fromknown or commercially available starting materials and reagents by oneskilled in the art of organic synthesis.

All reagents were of commercial grade and were used as received withoutfurther purification, unless otherwise stated. Commercially availableanhydrous solvents were used for reactions conducted under inertatmosphere. Reagent grade solvents were used in all other cases, unlessotherwise specified. Column chromatography was performed on silica gel60 (35-70 μm). Thin layer chromatography was carried out usingpre-coated silica gel F-254 plates (thickness 0.25 mm). ¹H NMR spectrawere recorded on a Bruker Advance 300 NMR spectrometer (300 MHz), anAgilent 400 MHz NMR spectrometer, or a 500 MHz NMR. Chemical shifts (6)for ¹H NMR spectra were reported in parts per million (ppm) relative totetramethylsilane (δ 0.00) or the appropriate residual solvent peak,i.e. CHCl₃ (δ 7.27), as internal reference. Multiplicities were given assinglet (s), doublet (d), doublet of quartets (dq), triplet (t), quartet(q), quintuplet (quin), multiplet (m) and broad (br). Electrospray MSspectra were obtained on a Waters platform LC/MS spectrometer or withWaters Acquity H-Class UPLC coupled to a Waters Mass detector 3100spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mmID×50 mm L, Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×30 mm L, orWaters Xterra® MS 5 μm C18, 100×4.6 mm. The methods were using eitherCH₃CN/H₂O gradients (H₂O contains either 0.1% CF₃CO₂H or 0.1% NH₃) orCH₃OH/H₂O gradients (H₂O contains 0.05% CF₃CO₂H). Microwave heating wasperformed with a Biotage® Initiator.

Reverse Phase Purification Methods Trifluoroacetic Acid Method

Samples were purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5μm 100 Å AXIA™ column (30 mm×75 mm). A gradient of acetonitrile (A) and0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-1.0 minute 5% A, 1.0-8.5 minute linear gradient 5-100% A,8.5-11.5 minute 100% A, 11.5-12.0 minute linear gradient 95-5% A).

Prep LC/MS Method TFA6

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, ata flow rate of 40 mL/minute (0-0.5 minute 15% A, 0.5-8.0 minute lineargradient 15-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A,9.0-9.1 minute linear gradient 100-15% A, 9.1-10 minute 15% A). A custompurification system was used, consisting of the following modules:Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis155 detector; Gilson 506C interface box; Gilson FC204 fractioncollector; Agilent G1968D Active Splitter; and Thermo MSQ Plus massspectrometer. The system was controlled through a combination of ThermoXcalibur 2.0.7 software and a custom application written in-house usingMicrosoft Visual Basic 6.0.

Prep LC/MS Method TFA8

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, ata flow rate of 40 mL/minute (0-0.5 minute 35% A, 0.5-8.0 minute lineargradient 35-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A,9.0-9.1 minute linear gradient 100-35% A, 9.1-10 minute 35% A). A custompurification system was used, consisting of the following modules:Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis155 detector; Gilson 506C interface box; Gilson FC204 fractioncollector; Agilent G1968D Active Splitter; and Thermo MSQ Plus massspectrometer. The system was controlled through a combination of ThermoXcalibur 2.0.7 software and a custom application written in-house usingMicrosoft Visual Basic 6.0.

Prep LC/MS Method TFA10

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, ata flow rate of 30 mL/minute (0-0.2 minute 5% A, 0.2-3.0 minute lineargradient 5-100% A, 4.1-4.5 minute 100-5% A, 4.5-5.0 minute 5% A). Acustom purification system was used, consisting of the followingmodules: Gilson 305 and 306 pumps; Gilson 806 Manometric module; GilsonUV/Vis 155 detector; Gilson 506C interface box; Gilson FC204 fractioncollector; Agilent G1968D Active Splitter; and Thermo MSQ Plus massspectrometer. The system was controlled through a combination of ThermoXcalibur 2.0.7 software and a custom application written in-house usingMicrosoft Visual Basic 6.0.

Prep LC/MS Method AA6

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at aflow rate of 40 mL/minute (0-0.5 minute 15% A, 0.5-8.0 minute lineargradient 15-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A,9.0-9.1 minute linear gradient 100-15% A, 9.1-10 minute 15% A). A custompurification system was used, consisting of the following modules:Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis155 detector; Gilson 506C interface box; Gilson FC204 fractioncollector; Agilent G1968D Active Splitter; and Thermo MSQ Plus massspectrometer. The system was controlled through a combination of ThermoXcalibur 2.0.7 software and a custom application written in-house usingMicrosoft Visual Basic 6.0.

Prep LC/MS Method AA7

Samples were purified by reverse phase preparative HPLC on a Phenomenex®Luna® C8(2) 5 m 100 Å AXIA™ column (50 mm×21.2 mm). A gradient ofacetonitrile (A) and 0.1% ammonium acetate in water (B) was used, at aflow rate of 40 mL/minute (0-0.5 minute 25% A, 0.5-8.0 minute lineargradient 25-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A,9.0-9.1 minute linear gradient 100-25% A, 9.1-10 minute 25% A). A custompurification system was used, consisting of the following modules:Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis155 detector; Gilson 506C interface box; Gilson FC204 fractioncollector; Agilent G1968D Active Splitter; and Thermo MSQ Plus massspectrometer. The system was controlled through a combination of ThermoXcalibur 2.0.7 software and a custom application written in-house usingMicrosoft Visual Basic 6.0.

Example I-11-(5-bromo-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamideExample I-1A (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide

A 250-mL round bottom flask equipped with a magnetic stir bar under anatmosphere of nitrogen was treated with indium(III) chloride (0.323 g,1.460 mmol) and acid washed zinc (7.32 g, 112 mmol) and then purged withnitrogen for several minutes. Tetrahydrofuran (70 mL) was added. Bromine(0.201 mL, 3.93 mmol) was added in a single portion resulting in a mildtemperature increase. The mixture was warmed to 55° C. and stirredrapidly under a nitrogen atmosphere. In a separate flask, a solution ofmethyl 1-bromocyclopropanecarboxylate (6.54 mL, 56.2 mmol) intetrahydrofuran (30 mL) was purged with nitrogen for 10 minutes. Themixture was added to the zinc slurry in a single portion via a cannula.The reaction was warmed at 55° C. for one hour. Using the titrationmethod described in Knochel, P.; Krasovskiy. A., Synthesis 2006 (2006(05), 0890-0891, the solution was determined to be 0.47 M and was usedimmediately in the next step.

Example I-1B Methyl 1-(2-methoxyphenyl)cyclopropane-1-carboxylate

Into a 500 mL round bottom flask was addedtris(dibenzylideneacetone)dipalladium(0) (0.086 g, 0.094 mmol),1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (0.133 g,0.187 mmol) and tetrahydrofuran (144 mL) under nitrogen.1-Bromo-2-methoxybenzene (2.313 mL, 18.71 mmol) was added and theresulting solution was treated with a 0.47 M solution of Example I-1A((1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide) (47.8 mL, 22.46 mmol)slowly over 10 minutes. The mixture was stirred at ambient temperatureovernight. The reaction was quenched with saturated aqueous NH₄Clsolution (50 mL) and extracted with ethyl acetate (200 mL). The organiclayer was washed with saturated aqueous NH₄Cl solution, dried oversodium sulfate, filtered, and concentrated. The crude residue waspurified by chromatography on silica gel eluting with a gradient of0-20% ethyl acetate in heptanes to provide the title compound. ¹H NMR(400 MHz, CDCl₃) δ ppm 7.30-7.25 (m, 1H), 7.20 (dd, J=1.7, 7.5 Hz, 1H),6.92 (dd, J=1.1, 7.5 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 3.84 (s, 3H), 3.61(d, J=0.8 Hz, 3H), 1.60 (q, J=3.9 Hz, 2H), 1.11 (q, J=4.1 Hz, 2H).

Example I-1C Methyl1-(5-bromo-2-methoxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-1B (methyl1-(2-methoxyphenyl)cyclopropanecarboxylate) (3.88 g, 18.81 mmol) andbenzyltrimethylammonium tribromide (7.72 g, 19.80 mmol) intetrahydrofuran (58.8 mL) and degassed water (35.3 mL) was stirred atambient temperature for 16 hours. The mixture was concentrated in vacuoand the resulting aqueous residue was extracted with methyl tert-butylether (850 mL). The organic layer was dried (Na₂SO₄), filtered through apad of silica gel and concentrated to give the title compound. ¹H NMR(501 MHz, CDCl₃) δ ppm 7.38 (dd, J=8.7, 2.5 Hz, 1H), 7.32 (d, J=2.5 Hz,1H), 6.77 (d, J=8.7 Hz, 1H), 3.84 (s, 3H), 3.63 (s, 3H), 1.64-1.61 (m,2H), 1.14-1.09 (m, 2H).

Example I-1D 1-(5-bromo-2-methoxyphenyl)cyclopropane-1-carboxylic Acid

Example I-1C (48 mg, 0.17 mmol) was dissolved in tetrahydrofuran (600μL) and methanol (600 μL), treated with 3 M aqueous NaOH (300 μL) andheated at 50° C. for three hours. The reaction mixture was allowed tocool to ambient temperature and was concentrated. The residue waspartitioned between 1 M aqueous citric acid (2 mL) and methyl tert-butylether. The separated aqueous phase was extracted with additional methyltert-butyl ether. The combined organic phases were washed with brine,dried (Na₂SO₄), filtered, and concentrated. The crude material wasdissolved in methyl tert-butyl ether, washed twice with water and oncewith brine, dried (Na₂SO₄), filtered, and concentrated to provide thetitle compound. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆) δ ppm 7.40 (dd,J=8.7, 2.6 Hz, 1H), 7.31 (d, J=2.6 Hz, 1H), 6.93 (d, J=8.7 Hz, 1H), 3.77(s, 3H), 1.41-1.38 (m, 2H), 1.06-1.03 (m, 2H). MS (ESI−) m/z 269/271(M−H)⁻.

Example I-1E1-(5-bromo-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

To a solution of Example I-1D(1-(5-bromo-2-methoxyphenyl)cyclopropanecarboxylic acid) (43 mg, 0.16mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61mg, 0.32 mmol) and 4-dimethylaminopyridine (22 mg, 0.18 mmol) inanhydrous dichloromethane (500 μL) was added naphthalene-1-sulfonamide(40 mg, 0.19 mmol). The mixture was stirred at ambient temperature for16 hours and was purified by reverse-phase HPLC [Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 70% gradient ofacetonitrile in 0.1% aqueous trifluoroacetic acid] to give the titlecompound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.67 (s, 1H),8.54-8.50 (m, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.24 (dd, J=7.4, 1.3 Hz, 1H),8.13-8.09 (m, 1H), 7.70-7.66 (m, 3H), 7.43 (dd, J=8.7, 2.5 Hz, 1H), 7.26(d, J=2.5 Hz, 1H), 6.81 (d, J=8.7 Hz, 1H), 3.27 (s, 3H), 1.25-1.22 (m,2H), 0.99-0.96 (m, 2H). MS (ESI) m/z=460/462 (M+H)⁺.

Example I-21-(5-cyclobutyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

Example I-1 (30 mg, 0.065 mmol, 1.0 eq) was dissolved in tetrahydrofuran(0.4 mL). PEPPSI IPentCl(dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),5.60 mg, 0.0065 mmol, 0.1 eq) in tetrahydrofuran (0.2 mL) was added,followed by the addition of cyclobutylzinc bromide (0.5 M intetrahydrofuran, 0.4 mL, 0.2 mmol, 3.0 eq). The reaction was stirred for16 hours at ambient temperature. The reaction was purified directly viapreparative reverse phase HPLC/MS method trifluoroacetic acid 8 toafford the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm8.56-8.52 (m, 1H), 8.26-8.22 (m, 2H), 8.13-8.09 (m, 1H), 7.70-7.66 (m,3H), 7.17-7.11 (m, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.81 (d, J=8.5 Hz, 1H),3.43 (p, J=8.8 Hz, 1H), 3.34 (s, 3H), 2.29-2.19 (m, 2H), 2.11-1.99 (m,2H), 1.99-1.88 (m, 1H), 1.83-1.74 (m, 1H), 1.27-1.23 (m, 2H), 0.96-0.92(m, 2H). MS (APCI) m/z 436.1 (M+H)⁺.

Example I-31-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-3A 2-(5-cyclobutyl-2-methoxypyridin-3-yl)acetonitrile

3-(Bromomethyl)-5-cyclobutyl-2-methoxypyridine (3.6 g, 14.05 mmol) inethanol (60 mL) was treated with a solution of sodium cyanide (0.758 g,15.46 mmol) in water (6.00 mL). The mixture was stirred at 50° C. forone hour. The solvent was removed under reduced pressure. The residuewas dissolved in dichloromethane and was washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified viachromatography on a 50 g silica gel cartridge, eluting with ethylacetate/methanol (9:1) in heptane using a 0-50% at gradient to providethe title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.96 (dd,J=2.2, 0.8 Hz, 1H), 7.55 (dq, J=2.3, 0.8 Hz, 1H), 3.96 (s, 3H), 3.66 (t,J=0.8 Hz, 2H), 3.50 (dtdt, J=10.2, 9.5, 8.0, 0.8 Hz, 1H), 2.42-2.28 (m,2H), 2.17-1.99 (m, 3H), 1.94-1.83 (m, 1H). MS (trifluoroaceticacid/APCI+) m/z 203 (M+H)⁺.

Example I-3B1-(5-cyclobutyl-2-methoxypyridin-3-yl)cyclopropanecarbonitrile

To 2-(5-cyclobutyl-2-methoxypyridin-3-yl)acetonitrile (2.5 g, 12.36mmol) in N,N-dimethylformamide (25 mL) was added sodium hydride (1.483g, 37.1 mmol) slowly and the resulting mixture was stirred at ambienttemperature until the bubbling subsided. To the mixture was slowly added1,2-dibromoethane (1.278 mL, 14.83 mmol) and stirring was continued atambient temperature for one hour. Dichloromethane (50 mL) was added. Themixture was washed with brine, dried over MgSO₄, filtered, andconcentrated. Purification via chromatography on a 25 g silica gelcartridge, eluting with ethyl acetate/methanol in hexane at 0-60%,provided the title compound. MS (APCI+) m/z 229 (M+H)⁺.

Example I-3C1-(5-cyclobutyl-2-methoxypyridin-3-yl)cyclopropanecarboxylic Acid

To 1-(5-cyclobutyl-2-methoxypyridin-3-yl)cyclopropanecarbonitrile (1.7g, 7.45 mmol) in ethanol (10 mL) was added sodium hydroxide (2.5 g, 62.5mmol) in water (10 mL) slowly and the resulting mixture was stirred at90° C. for 16 hours. The solvent was removed and the residue waspurified via chromatography on a 25 g cartridge, eluting with ethylacetate/methanol (1:1) in hexane (0-60%) to provide the title compound.¹H NMR (501 MHz, chloroform-d) δ ppm 7.91 (dd, J=2.4, 0.8 Hz, 1H), 7.33(dd, J=2.4, 0.6 Hz, 1H), 3.94 (s, 3H), 3.50-3.39 (m, 1H), 2.37-2.26 (m,2H), 2.15-1.95 (m, 3H), 1.90-1.81 (m, 1H), 1.67 (q, J=4.1 Hz, 2H), 1.15(q, J=4.2 Hz, 2H). MS (ESI+) m/z 248 (M+H)⁺.

Example I-3D1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-((2-methylquinolin-5-yl)sulfonyl)cyclopropanecarboxamide

A mixture of Example I-3C (60 mg, 0.243 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (75 mg,0.485 mmol) and N,N-dimethylpyridin-4-amine (59.3 mg, 0.485 mmol) indichloromethane (2 mL) was stirred at 50° C. for 2 hours. The reactionmixture was loaded onto a 12 g silica gel cartridge, eluting withmethanol in ethyl acetate at 0-10% gradient to provide the titlecompound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 8.89 (d, J=8.8Hz, 1H), 7.93 (d, J=7.7 Hz, 2H), 7.80 (d, J=2.4 Hz, 1H), 7.66 (t, J=7.9Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.5 Hz, 1H), 3.61 (s, 3H),3.42 (t, J=8.8 Hz, 1H), 2.66 (s, 3H), 2.24 (dtd, J=10.5, 8.1, 2.5 Hz,2H), 2.11-2.00 (m, 2H), 2.00-1.89 (m, 1H), 1.84-1.77 (m, 1H), 1.18-1.11(m, 2H), 0.66 (s, 2H). MS (ESI+) m/z 452 (M+H)+.

Example I-41-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of Example I-3C (60 mg, 0.243 mmol) andNi-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (75 mg,0.485 mmol) and N,N-dimethylpyridin-4-amine (59.3 mg, 0.485 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes, and quinoline-5-sulfonamide (55.6 mg, 0.267 mmol) was added.The mixture was stirred at 50° C. for 2 hours. The solvent was removedand the residue was purified via reverse phase HPLC (C18, CH₃CN/H₂O(0.1% trifluoroacetic acid)=5-95%, 20 minutes) to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.81 (s, 1H),9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.95 (dt, J=8.9, 1.2 Hz, 1H), 8.41-8.28(m, 2H), 8.02-7.91 (m, 2H), 7.71 (dd, J=8.8, 4.2 Hz, 1H), 7.43 (d, J=2.3Hz, 1H), 3.46 (t, J=8.9 Hz, 1H), 3.41 (s, 3H), 2.26 (qt, J=8.1, 2.5 Hz,2H), 2.12 (pd, J=9.1, 8.7, 2.5 Hz, 2H), 2.02-1.79 (m, 2H), 1.28 (q,J=4.3 Hz, 2H), 1.02 (q, J=4.4 Hz, 2H). MS (ESI+) m/z 438 (M+H)⁺.

Example I-51-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

A mixture of Example I-3C (60 mg, 0.243 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (75 mg,0.485 mmol) and N,N-dimethylpyridin-4-amine (59.3 mg, 0.485 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. Naphthalene-1-sulfonamide (55.3 mg, 0.267 mmol) was added. Themixture was stirred at 50° C. for two hours. The solvent was removed,and the residue was dissolved in methanol (2 mL) and filtered through asyringe filter. The filtrate was purified via reverse phase HPLC (C18,CH₃CN/H₂O (0.1% trifluoroacetic acid), 5-95%, 20 minutes) to provide thetitle compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.71 (s,1H), 8.59-8.49 (m, 1H), 8.32-8.21 (m, 2H), 8.17-8.08 (m, 1H), 7.92 (d,J=2.3 Hz, 1H), 7.74-7.64 (m, 3H), 7.41 (d, J=2.4 Hz, 1H), 3.47 (q, J=8.8Hz, 1H), 3.42 (s, 3H), 2.25 (dtt, J=10.9, 7.8, 2.8 Hz, 2H), 2.18-2.06(m, 2H), 2.03-1.90 (m, 1H), 1.87-1.77 (m, 1H), 1.28 (q, J=4.3 Hz, 2H),1.00 (q, J=4.4 Hz, 2H). MS (ESI+) m/z 437 (M+H)⁺.

Example I-61-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of Example I-3C (60 mg, 0.243 mmol) andNi-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (75 mg,0.485 mmol) and N,N-dimethylpyridin-4-amine (59.3 mg, 0.485 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. 1,2,3,4-Tetrahydroisoquinoline-5-sulfonamide (56.7 mg, 0.267mmol) was added. The mixture was stirred at 50° C. for two hours. Thesolvent was removed and the residue was dissolved in methanol (2 mL).The mixture was filtered through a syringe filter. The filtrate waspurified via reverse phase HPLC (C18, CH₃CN/H₂O (0.1% trifluoroaceticacid)=5-95%, 20 minutes) to provide the title compound. ¹H NMR (400 MHz,dimethyl sulfoxide-d₆) δ ppm 11.22 (s, 1H), 7.94 (d, J=2.3 Hz, 1H), 7.47(d, J=2.3 Hz, 1H), 7.08-6.97 (m, 2H), 6.69 (dd, J=7.4, 2.0 Hz, 1H), 6.14(s, 1H), 3.77 (s, 3H), 3.46 (p, J=8.8 Hz, 1H), 3.18 (t, J=5.5 Hz, 2H),2.88 (t, J=6.4 Hz, 2H), 2.26 (qt, J=8.1, 2.5 Hz, 2H), 2.18-2.06 (m, 2H),1.96 (tq, J=10.5, 8.4 Hz, 1H), 1.88-1.79 (m, 1H), 1.75 (dt, J=11.1, 5.6Hz, 2H), 1.38 (q, J=4.3 Hz, 2H), 1.06 (q, J=4.4 Hz, 2H). MS (ESI+) m/z442 (M+H)⁺.

Example I-71-(2,6-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamideExample I-7A methyl 1-(2,6-dimethoxyphenyl)cyclopropane-1-carboxylate

2-Bromo-1,3-dimethoxybenzene (80 mg, 0.369 mmol) was dissolved in drytetrahydrofuran (4.2 mL) and Q-Phos(pentaphenyl(di-tert-butylphosphino)ferrocene, 5.24 mg, 7.37 μmol) andPd(dba)₂ (tris(dibenzylideneacetone)dipalladium(0), 4.24 mg, 7.37 μmol)were added. A freshly-prepared solution of 0.26 M Example I-1A((1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide) in tetrahydrofuran(2.078 mL, 0.553 mmol) was added dropwise. The reaction was stirred forthree hours at ambient temperature, at which point the starting materialwas consumed. The reaction was quenched with saturated aqueous ammoniumchloride (0.5 mL) and extracted with methyl tert-butyl ether. Theorganic phase was concentrated and the crude residue was chromatographedon silica (0-40% methyl tert-butyl ether/heptanes) to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.21 (t, J=8.4 Hz, 1H), 6.54 (d,J=8.4 Hz, 2H), 3.80 (s, 6H), 3.58 (s, 3H), 1.68-1.64 (m, 2H), 1.14-1.11(m, 2H). MS (ESI) m/z=237 (M+H)⁺.

Example I-7B 1-(2,6-dimethoxyphenyl)cyclopropane-1-carboxylic Acid

Example I-7A (64 mg, 0.27 mmol) was added to isopropanol (1.5 mL),treated with 3 M aqueous NaOH (500 μL) and heated at 70° C. for 24hours. Additional 3 M aqueous NaOH (200 μL) was added and the reactionmixture was heated at 70° C. another five hours. The mixture was cooledto ambient temperature, acidified with trifluoroacetic acid andextracted with methyl tert-butyl ether. The combined extracts werewashed with 1 M aqueous citric acid and concentrated. The residue wasdissolved in ethyl acetate and the mixture was washed twice with water,dried (Na₂SO₄), filtered, and concentrated to provide the impure titlecompound which was used in the next step without further purification.¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 7.19 (t, J=8.4 Hz, 1H),6.60 (d, J=8.4 Hz, 2H), 3.75 (s, 6H), 1.50-1.43 (m, 2H), 1.00-0.93 (m,2H). MS (DCI) m/z 240 (M+NH₄)⁺.

Example I-7C1-(2,6-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

To a mixture of Example I-7B(1-(2,6-dimethoxyphenyl)cyclopropanecarboxylic acid) (34 mg, 0.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) in anhydrousdichloromethane (500 μL) was added naphthalene-1-sulfonamide (44 mg,0.21 mmol). The mixture was stirred at ambient temperature for 16 hours,concentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 70% gradient ofacetonitrile in 0.1% aqueous trifluoroacetic acid] to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.07 (s, 1H),8.57-8.52 (m, 1H), 8.28 (dd, J=8.3, 1.1 Hz, 1H), 8.23 (dd, J=7.5, 1.2Hz, 1H), 8.14-8.08 (m, 1H), 7.73-7.64 (m, 3H), 7.25 (t, J=8.4 Hz, 1H),6.59 (d, J=8.4 Hz, 2H), 3.58 (s, 6H), 1.40-1.36 (m, 2H), 0.92-0.88 (m,2H). MS (ESI) m/z 412 (M+H)⁺.

Example I-81-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamideExample I-8A1-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylic Acid

To 3-bromo-2-methoxy-5-(trifluoromethyl)pyridine [CAS #124432-63-9] (2g, 7.81 mmol) in 20 mL of dry tetrahydrofuran was added Q-Phos(pentaphenyl(di-tert-butylphosphino)ferrocene, 0.122 g, 0.172 mmol) andPd(dba)₂ (tris(dibenzylideneacetone)dipalladium(0), 0.143 g, 0.156mmol). A solution of freshly-prepared(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (2.86 g, 11.72 mmol) intetrahydrofuran (0.5 mmol/mL, 30 mL) was added via a stainless steelcannula with nitrogen pressure. The mixture was stirred at ambienttemperature for one hour. Dichloromethane (30 mL) and saturated aqueousNH₄Cl (10 mL) was added and the organic layer was washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedvia chromatography on a 50 g silica gel cartridge, eluting with ethylacetate/methanol (9:1) in heptane at a 0-50% gradient to provide methyl1-(2-methoxy-5-(trifluoromethyl)-pyridin-3-yl)cyclopropanecarboxylate,HTP-LC/MS (APCI), m/z=276 (M+H)⁺. Methyl1-(2-methoxy-5-(trifluoromethyl)-pyridin-3-yl)cyclopropanecarboxylatewas dissolved in methanol (6 mL) and lithium hydroxide (1.096 g, 45.8mmol) in water (1 mL). The mixture was stirred at 50° C. for 3 hours.The solvent was removed and the residue was adjusted pH to 1-2 by adding2 N aqueous HCl. The mixture was extracted using dichloromethane andmethanol (10:1). The extracts were washed with brine, dried over MgSO₄,filtered, concentrated to dryness, and dried in an oven to provide thetitle compound. HTP-LC/MS (APCI+) m/z 262.18 (M+H)⁺.

Example I-8B1-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-N-(naphthalen-1-ylsulfonyl)cyclopropanecarboxamide

A mixture of1-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylic acid(65 mg, 0.249 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (77 mg,0.498 mmol) and N,N-dimethylpyridin-4-amine (60.8 mg, 0.498 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. Naphthalene-1-sulfonamide (56.7 mg, 0.274 mmol) was added. Themixture was stirred at 45° C. for 2 hours. The solvent was removed andthe residue was dissolved in methanol (3 mL) and filtered. Purificationvia reverse phase HPLC (C18, CH₃CN/H₂O (0.1% trifluoroacetic acid),5-95%, 20 minutes) provided the title compound. ¹H NMR (400 MHz,dimethyl sulfoxide-d₆) δ ppm 11.86 (s, 1H), 8.51 (dd, J=2.4, 1.2 Hz,1H), 8.49-8.44 (m, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.26 (dd, J=7.5, 1.3 Hz,1H), 8.17-8.10 (m, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.75-7.63 (m, 3H), 3.44(s, 3H), 1.30 (q, J=4.3 Hz, 2H), 1.09 (q, J=4.4 Hz, 2H). MS (ESI+) m/z451 (M+H)⁺.

Example I-91-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide

A mixture of Example I-26A (300 mg, 1.052 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (327 mg,2.104 mmol) and N,N-dimethylpyridin-4-amine (257 mg, 2.104 mmol) indichloromethane (6 mL) was stirred at ambient temperature for 30minutes. 1,2,3,4-Tetrahydroquinoline-5-sulfonamide (246 mg, 1.157 mmol)was added. The mixture was stirred at 45° C. for 3 hours. The solventwas removed and the residue was dissolved in methanol (3 mL) andfiltered. Purification via reverse phase HPLC (C18, CH₃CN/H₂O (0.1%trifluoroacetic acid), 5-95%, 20 minutes) provided the title compound.¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.12 (s, 1H), 7.55 (d,J=2.5 Hz, 1H), 7.44 (dd, J=8.7, 2.4 Hz, 1H), 7.06 (dd, J=7.8, 1.3 Hz,1H), 7.01 (t, J=7.9 Hz, 1H), 6.91 (d, J=8.6 Hz, 1H), 6.74-6.65 (m, 1H),6.09 (s, 1H), 3.48 (s, 3H), 3.14-3.08 (m, 2H), 2.67-2.60 (m, 2H),2.60-2.53 (m, 2H), 2.21 (dt, J=12.3, 8.7 Hz, 2H), 1.73 (q, J=7.8 Hz,2H), 1.61 (p, J=6.2 Hz, 2H). MS (ESI+) m/z 481 (M+H)⁺.

Example I-101-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide

A mixture of Example I-26B (70 mg, 0.269 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (83 mg,0.538 mmol) and N,N-dimethylpyridin-4-amine (65.7 mg, 0.538 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. 1,2,3,4-Tetrahydroquinoline-5-sulfonamide (62.8 mg, 0.296 mmol)was added. The mixture was stirred at 45° C. for 16 hours. The solventwas removed and the residue was dissolved in methanol (3 mL) andfiltered. Purification via reverse phase HPLC (C18, CH₃CN/H₂O (0.1%trifluoroacetic acid), 5-95%, 20 minutes) provided the title compound.¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 10.85 (s, 1H), 7.23 (d,J=2.3 Hz, 1H), 7.13 (dd, J=8.4, 2.2 Hz, 1H), 7.07 (dd, J=7.8, 1.3 Hz,1H), 7.00 (t, J=7.9 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.68 (dd, J=8.0,1.4 Hz, 1H), 3.49 (s, 4H), 3.07 (t, J=5.5 Hz, 2H), 2.61 (dddd, J=12.5,7.9, 5.7, 2.4 Hz, 2H), 2.53 (d, J=6.4 Hz, 2H), 3.26 (s, 3H), 3.50-3.44(ddt, J=14.9, 10.6, 6.0 Hz, 1H), 2.12 (pd, J=9.4, 8.7, 5.5 Hz, 2H),2.02-1.90 (m, 1H), 1.87-1.67 (m, 3H), 1.55 (p, J=6.1 Hz, 2H). MS (ESI+)m/z 455 (M+H)⁺.

Example I-111-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

In a 4 mL vial was added Example I-1D (75 mg, 0.277 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (106 mg, 0.553 mmol), and N,N-dimethylpyridin-4-amine(37.2 mg, 0.304 mmol) in dichloromethane (2 mL).1,2,3,4-Tetrahydroquinoline-5-sulfonamide (64.6 mg, 0.304 mmol) wasadded. The reaction was stirred overnight at ambient temperature. Thesolvent was removed under nitrogen and the residue was dissolved inmethanol and purified directly via preparative reverse phase HPLC/MSmethod trifluoroacetic acid 8 to provide the title compound. ¹H NMR (501MHz, dimethyl sulfoxide-d₆:D20=9:1 (v/v)) δ ppm 7.46 (dd, J=8.7, 2.5 Hz,1H), 7.32 (d, J=2.5 Hz, 1H), 7.06-6.99 (m, 2H), 6.96 (d, J=8.8 Hz, 1H),6.70 (dd, J=6.2, 3.1 Hz, 1H), 3.70 (s, 3H), 3.21-3.14 (m, 2H), 2.86 (t,J=6.4 Hz, 2H), 1.77 (p, J=6.3 Hz, 2H), 1.36 (q, J=4.4 Hz, 2H), 1.06-1.02(m, 2H). MS (APCI+) m/z 464.9 (M+H)⁺.

Example I-121-(5-cyclopropyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamideExample I-12A Methyl1-(5-cyclopropyl-2-methoxyphenyl)cyclopropane-1-carboxylate

A mixture of Example I-1C (methyl1-(5-bromo-2-methoxyphenyl)cyclopropanecarboxylate) (48 mg, 0.168 mmol),potassium cyclopropyltrifluoroborate (29.9 mg, 0.202 mmol),palladium(II) acetate (3.78 mg, 0.017 mmol), butyldi-1-adamantylphosphine (9.05 mg, 0.025 mmol), and Cs₂CO₃ (165 mg, 0.505mmol) was added to toluene (0.9 mL) and water (0.11 mL). The mixture wastreated with a stream of nitrogen for 1 minute. The mixture was stirredat 80° C. for 23 hours, cooled and partitioned between ethyl acetate (30mL) and 1 M aqueous HCl (10 mL). The layers were separated and theaqueous layer was extracted with ethyl acetate (15 mL). The combinedethyl acetate layers were washed with brine, dried (MgSO₄), filtered,concentrated and chromatographed on silica gel, eluting with a gradientof 5% to 25% ethyl acetate in heptanes to provide the title compound. ¹HNMR (501 MHz, CDCl₃) δ ppm 6.97-6.93 (m, 2H), 6.77 (d, J=8.1 Hz, 1H),3.79 (s, 3H), 3.60 (s, 3H), 1.83 (tt, J=5.1, 8.4 Hz, 1H), 1.59-1.57 (m,2H), 1.11-1.08 (m, 2H), 0.91-0.86 (m, 2H), 0.63-0.59 (m, 2H). LC/MS(APCI+) m/z 247 (M+H)⁺.

Example I-12B 1-(5-cyclopropyl-2-methoxyphenyl)cyclopropane-1-carboxylicAcid

A solution of Example I-12A (methyl1-(5-cyclopropyl-2-methoxyphenyl)cyclopropanecarboxylate) (34.2 mg,0.139 mmol) in tetrahydrofuran (˜1.5 mL) was diluted with methanol (˜1.5mL), treated with 1 M aqueous NaOH (˜1 mL), and stirred at ambienttemperature for 30 minutes. The mixture was heated to 60° C. for 20minutes, treated with 3 M aqueous NaOH (˜1 mL), heated to 60° C. for 1hour, cooled, and partitioned between methyl tert-butyl ether (40 mL)and 1 M aqueous HCl (15 mL). The methyl tert-butyl ether layer waswashed with brine, dried (MgSO₄), filtered, and concentrated to providethe title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.97-6.94 (m, 2H),6.77 (d, J=8.9 Hz, 1H), 3.81 (s, 3H), 1.82 (tt, J=5.1, 8.4 Hz, 1H), 1.63(q, J=4.1 Hz, 2H), 1.16 (q, J=4.1 Hz, 2H), 0.90-0.85 (m, 2H), 0.63-0.57(m, 2H).

Example I-12C1-(5-cyclopropyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

To a solution of Example I-12B(1-(5-cyclopropyl-2-methoxyphenyl)cyclopropanecarboxylic acid) (15 mg,0.065 mmol), EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride) (24.76 mg, 0.129 mmol) and naphthalene-1-sulfonamide(14.72 mg, 0.071 mmol) in N,N-dimethylformamide (0.3 mL) was added4-dimethylaminopyridine (8.68 mg, 0.071 mmol). The mixture was stirredfor 2 days. The mixture was partitioned between methyl tert-butyl ether(75 mL) and 1 M aqueous HCl (15 mL). The methyl tert-butyl ether layerwas washed with 0.2 M aqueous HCl (˜10 mL), washed with brine, dried(MgSO₄), filtered, concentrated and chromatographed on silica gel,eluting with a gradient of 10% to 100% [9:1 dichloromethane: [200:1:1ethyl acetate:HCOOH:H₂O]] in heptanes to provide the title compound. ¹HNMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.41 (s, 1H), 8.58-8.53 (m,1H), 8.30-8.21 (m, 2H), 8.13-8.08 (m, 1H), 7.70-7.65 (m, 3H), 6.93 (dd,J=2.3, 8.4 Hz, 1H), 6.83 (d, J=2.3 Hz, 1H), 6.74 (d, J=8.4 Hz, 1H), 3.31(s, 3H), 1.84 (tt, J=5.1, 8.4 Hz, 1H), 1.25-1.21 (m, 2H), 0.93 (bs, 2H),0.89-0.84 (m, 2H), 0.62-0.57 (m, 2H). LC/MS (APCI+) m/z 422 (M+H)⁺.

Example I-131-(5-cyclopropyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of Example I-12B(1-(5-cyclopropyl-2-methoxyphenyl)cyclopropanecarboxylic acid) (15 mg,0.065 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(24.76 mg, 0.129 mmol) and quinoline-5-sulfonamide (14.79 mg, 0.071mmol) in N,N-dimethylformamide (0.3 mL) was added4-dimethylaminopyridine (8.68 mg, 0.071 mmol). The mixture was stirredfor 2 days at ambient temperature. The mixture was treated withadditional 4-dimethylaminopyridine (˜5 mg) and quinoline-5-sulfonamide(˜10 mg) and stirred at ambient temperature for 2 hours. The mixture waspartitioned between methyl tert-butyl ether (75 mL) and 1 M aqueous HCl(15 mL). The methyl tert-butyl ether layer was washed with 0.2 M aqueousHCl (˜10 mL), washed with brine, dried (MgSO₄), filtered, concentratedand chromatographed on silica gel, eluting with a gradient of 25% to100% [200:1:1 ethyl acetate:HCOOH:H₂O] in heptanes to provide the titlecompound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.56 (s, 1H),9.04 (dd, J=1.6, 4.1 Hz, 1H), 8.97 (dd, J=1.1, 8.8 Hz, 1H), 8.35-8.29(m, 2H), 7.93 (t, J=7.9 Hz, 1H), 7.70 (dd, J=4.2, 8.8 Hz, 1H), 6.93 (dd,J=2.3, 8.4 Hz, 1H), 6.84 (d, J=2.3 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 3.31(s, 3H), 1.84 (tt, J=5.1, 8.5 Hz, 1H), 1.21 (q, J=4.2 Hz, 2H), 0.93 (s,2H), 0.89-0.85 (m, 2H), 0.62-0.58 (m, 2H). LC/MS (APCI+) m/z 423 (M+H)⁺.

Example I-141-{2-methoxy-5-[(propan-2-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-14A methyl1-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate

A mixture of Example I-1C (methyl1-(5-bromo-2-methoxyphenyl)cyclopropanecarboxylate) (0.31 g, 1.087mmol), potassium acetate (0.534 g, 5.44 mmol) and bis(pinacolato)diboron(0.828 g, 3.26 mmol) in dioxane (15 mL) was vacuum purged with nitrogenseveral times, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane, (0.089 g, 0.109 mmol) and heated for 16 hours at100° C. under nitrogen. The mixture was cooled and partitioned betweenmethyl tert-butyl ether (˜75 mL) and saturated aqueous Sodiumbicarbonate solution (15 mL). The layers were separated and the aqueouslayer was extracted with methyl tert-butyl ether (˜25 mL). The combinedmethyl tert-butyl ether layers were washed with brine, dried (MgSO₄),filtered, and concentrated. The residue was chromatographed on silicagel, eluting with a gradient of 10% to 30% [200:1:1 ethylacetate:HCOOH:H₂O] in heptanes to provide the title compound. ¹H NMR(501 MHz, CDCl₃) δ ppm 7.74 (dd, J=1.7, 8.2 Hz, 1H), 7.63 (d, J=1.7 Hz,1H), 6.86 (d, J=8.2 Hz, 1H), 3.85 (s, 3H), 3.58 (s, 3H), 1.58 (q, J=4.1Hz, 2H), 1.32 (s, 12H), 1.14 (q, J=4.1 Hz, 2H). LC/MS (APCI+) m/z 333(M+H)⁻.

Example I-14B Methyl1-(5-hydroxy-2-methoxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-14A (methyl1-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate)(136 mg, 0.409 mmol) in methanol (4 mL) was treated with 30% aqueoushydrogen peroxide (418 μl, 4.09 mmol) and stirred for 2 days at ambienttemperature. The mixture was partitioned between methyl tert-butyl ether(˜50 mL) and water (˜25 mL). The layers were separated. The methyltert-butyl ether layer was washed with 0.75 M aqueous solution of sodiumthiosulfate pentahydrate (5.1 mL, 4.09 mmol). The biphasic mixture wastreated with 1 M aqueous HCl until the aqueous layer was acidic. Themethyl tert-butyl ether layer was isolated, washed with brine, dried(MgSO₄), filtered, and concentrated to provide the title compound. ¹HNMR (501 MHz, CDCl₃) δ ppm 6.74-6.70 (m, 3H), 4.97 (s, 1H), 3.77 (s,3H), 3.61 (s, 3H), 1.59-1.57 (m, 2H), 1.10-1.08 (m, 2H).

Example I-14C Methyl1-(5-isopropoxy-2-methoxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-14B (methyl1-(5-hydroxy-2-methoxyphenyl)cyclopropanecarboxylate) (27 mg, 0.121mmol), cesium carbonate (198 mg, 0.607 mmol) and 2-bromopropane (57.0μl, 0.607 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at ambienttemperature for 1 hour, treated with sodium iodide (1.821 mg, 0.012mmol), heated to 60° C. for 30 minutes, cooled and partitioned betweenmethyl tert-butyl ether (30 mL) and water (15 mL). The layers wereseparated. The methyl tert-butyl ether layer was washed with water (10mL), washed with brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 10% to 30%ethyl acetate in heptanes to provide the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 6.77 (s, 3H), 4.42 (hept, J=6.1 Hz, 1H), 3.78 (s, 3H),3.61 (s, 3H), 1.58 (q, J=4.1 Hz, 2H), 1.31 (d, J=6.1 Hz, 6H), 1.10 (q,J=4.1 Hz, 2H).

Example I-14D 1-(5-isopropoxy-2-methoxyphenyl)cyclopropane-1-carboxylicAcid

A solution of Example I-14C (methyl1-(5-isopropoxy-2-methoxyphenyl)cyclopropanecarboxylate) (15 mg, 0.057mmol) in tetrahydrofuran (˜1.5 mL) was diluted with methanol (˜1.5 mL),treated with 3 M aqueous NaOH (˜1 mL) heated to 60° C. for 2 hours,cooled and partitioned between methyl tert-butyl ether (40 mL) and 1 Maqueous HCl (10 mL). The methyl tert-butyl ether layer was washed withbrine, dried (MgSO₄), filtered, and concentrated to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.79-6.76 (m, 3H), 4.40 (hept,J=6.0 Hz, 1H), 3.80 (s, 3H), 1.63 (q, J=4.1 Hz, 2H), 1.29 (d, J=6.1 Hz,6H), 1.16 (q, J=4.2 Hz, 2H).

Example I-14E1-{2-methoxy-5-[(propan-2-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of Example I-14D(1-(5-isopropoxy-2-methoxyphenyl)cyclopropanecarboxylic acid) (15 mg,0.060 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(22.98 mg, 0.120 mmol) and quinoline-5-sulfonamide (18.72 mg, 0.090mmol) in N,N-dimethylformamide (0.3 mL) was added4-dimethylaminopyridine (14.64 mg, 0.120 mmol). The mixture was stirredfor 80 minutes. The mixture was partitioned between methyl tert-butylether (50 mL) and 0.2 M aqueous HCl (15 mL). The methyl tert-butyl etherlayer was washed with 0.2 M aqueous HCl (˜10 mL), washed with brine,dried (MgSO₄), filtered, concentrated and chromatographed on silica gel,eluting with a gradient of 25% to 100% [200:1:1 ethyl acetate:HCOOH:H₂O]in heptanes to provide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.62 (bs, 1H), 9.04 (dd, J=1.5, 4.1 Hz, 1H), 8.98(d, J=8.7 Hz, 1H), 8.37-8.29 (m, 2H), 7.93 (t, J=7.9 Hz, 1H), 7.69 (dd,J=4.2, 8.8 Hz, 1H), 6.80 (dd, J=2.8, 8.9 Hz, 1H), 6.76 (d, J=8.8 Hz,1H), 6.66 (d, J=2.8 Hz, 1H), 4.47 (hept, J=6.0 Hz, 1H), 3.30 (s, 3H),1.23 (d, J=6.0 Hz, 6H), 1.22-1.19 (m, 2H), 0.97-0.91 (m, 2H). MS (APCI+)m/z 441 (M+H)⁺.

Example I-151-(2-methoxy-5-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamideExample I-15A 1-(2-methoxy-5-methylpyridin-3-yl)cyclopropanecarboxylicAcid

To 3-bromo-2-methoxy-5-methylpyridine [CAS #717843-56-6] (1.0 g, 4.95mmol) in 20 mL of dry tetrahydrofuran was added Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.077 g,0.109 mmol) and bis(dibenzylideneacetone)palladium (0.091 g, 0.099mmol). A solution of freshly-prepared(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (2.419 g, 9.90 mmol) intetrahydrofuran (0.45 mmol/mL, 17 mL) was added via a stainless steelcannula under nitrogen pressure. The mixture was stirred at ambienttemperature for 40 minutes. Dichloromethane and saturated aqueous NH₄Clwere added. The organic layer was washed with brine and concentrated.The residue was purified via chromatography on a 40 g silica gelcartridge, eluting with ethyl acetate in heptane at 0-50% gradient toyield methyl 1-(2-methoxy-5-methylpyridin-3-yl)cyclopropanecarboxylatewhich was dissolved in methanol (10 mL) and 6M aqueous lithium hydroxide(3 mL) and stirred at 50° C. for 15 hours. The solvent was removed, andwater (10 mL) was added. The aqueous layer was extracted with ethylacetate (10 mL×2). The aqueous layer was adjusted pH 1-2 and extractedwith dichloromethane (30 mL×3), and the extracts washed with brine,dried over MgSO₄ and concentrated to provide the title compound whichused in next step without further purification. MS (APCI+) m/z 208(M+H)⁺.

Example I-15B1-(2-methoxy-5-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

A mixture of 1-(2-methoxy-5-methylpyridin-3-yl)cyclopropanecarboxylicacid (50 mg, 0.241 mmol) from Example I-15A andNi-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (74.9 mg,0.483 mmol) and N,N-dimethylpyridin-4-amine (59.0 mg, 0.483 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes, and then naphthalene-1-sulfonamide (55.0 mg, 0.265 mmol) wasadded. The mixture was stirred at 45° C. for 3 hours. The solvent wasremoved and the residue was dissolved in methanol (3 mL) and filtered.The filtrate was purified by reverse-phase preparative HPLC on aPhenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). Agradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B)was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR(400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.67 (s, 1H), 8.49 (dt, J=7.1,3.6 Hz, 1H), 8.29-8.18 (m, 2H), 8.11-8.04 (m, 1H), 7.85 (d, J=2.2 Hz,1H), 7.71-7.61 (m, 3H), 7.32 (d, J=2.3 Hz, 1H), 3.36 (s, 3H), 2.17 (s,3H), 1.23 (q, J=4.3 Hz, 2H), 0.94 (q, J=4.4 Hz, 2H). MS(ESI+) m/z 397(M+H)⁺.

Example I-161-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example I-11 (60 mg, 0.13 mmol, 1.0 eq) was dissolved in tetrahydrofuran(0.5 mL). PEPPSI IPentCl(dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),11.2 mg, 0.013 mmol, 0.1 eq) in tetrahydrofuran (0.2 mL) was added.Cyclobutylzinc bromide (0.5 M in tetrahydrofuran, 0.77 mL, 0.39 mmol,3.0 eq) was added and the reaction was stirred overnight at ambienttemperature. The reaction mixture was purified directly via preparativereverse phase HPLC/MS method trifluoroacetic acid 7 to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D2O=9:1 (v/v)) ppm δppm 7.18 (dd, J=8.5, 2.2 Hz, 1H), 7.09-6.96 (m, 3H), 6.93 (d, J=8.5 Hz,1H), 6.72 (dd, J=6.5, 2.8 Hz, 1H), 3.70 (s, 3H), 3.43 (q, J=8.7 Hz, 1H),3.17 (t, J=5.4 Hz, 2H), 2.84 (t, J=6.3 Hz, 2H), 2.33-2.17 (m, 2H),2.15-1.71 (m, 6H), 1.38 (q, J=4.3 Hz, 2H), 1.03 (q, J=4.5 Hz, 2H). MS(APCI) m/z 441.1 (M+H)⁺.

Example I-171-(5-cyclobutyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example 1-18 (60 mg, 0.13 mmol, 1.0 eq) was dissolved in tetrahydrofuran(0.5 mL). PEPPSI IPentCl(dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),11.2 mg, 0.013 mmol, 0.1 eq) in tetrahydrofuran (0.2 mL) was added.Cyclobutylzinc bromide (0.5 M in tetrahydrofuran, 0.77 mL, 0.39 mmol,3.0 eq) was added and the reaction was stirred for 16 hours at ambienttemperature. The reaction mixture was purified directly via preparativereverse phase HPLC/MS method trifluoroacetic acid 8 to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 9.05 (dd, J=4.2,1.6 Hz, 1H), 8.96 (dt, J=8.8, 1.3 Hz, 1H), 8.36 (dt, J=8.5, 1.1 Hz, 1H),8.32 (dd, J=7.5, 1.3 Hz, 1H), 7.95 (dd, J=8.5, 7.5 Hz, 1H), 7.72 (dd,J=8.8, 4.2 Hz, 1H), 7.14 (dd, J=8.4, 2.3 Hz, 1H), 6.95 (d, J=2.2 Hz,1H), 6.80 (d, J=8.4 Hz, 1H), 3.46-3.34 (m, 1H), 3.31 (s, 3H), 2.29-2.17(m, 2H), 2.11-1.84 (m, 3H), 1.84-1.71 (m, 1H), 1.24 (q, J=4.4 Hz, 2H),0.95 (q, J=4.5 Hz, 2H). MS (APCI) m/z 437.0 (M+H)⁺.

Example I-181-(5-bromo-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example I-18 was prepared using the general procedure described inExample I-11, substituting quinoline-5-sulfonamide for1,2,3,4-tetrahydroquinoline-5-sulfonamide. ¹H NMR (400 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 9.07 (dd, J=4.2, 1.6 Hz, 1H), 8.94(dt, J=8.8, 1.3 Hz, 1H), 8.47-8.29 (m, 2H), 7.98 (dd, J=8.4, 7.5 Hz,1H), 7.74 (dd, J=8.8, 4.2 Hz, 1H), 7.45 (dd, J=8.7, 2.5 Hz, 1H), 7.28(d, J=2.5 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 3.29 (s, 3H), 1.25 (q, J=4.4Hz, 2H), 1.00 (q, J=4.5 Hz, 2H). MS (APCI) m/z 460.9 (M+H)+.

Example I-191-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide

Example I-19 was prepared using the general procedure described inExample I-11, substituting pyrazolo[1,5-a]pyridine-4-sulfonamide for1,2,3,4-tetrahydroquinoline-5-sulfonamide and Example I-3C for ExampleI-1D. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.96(dt, J=7.0, 1.0 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 7.93 (dd, J=2.4, 0.7Hz, 1H), 7.86 (dd, J=7.2, 1.0 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 7.10 (t,J=7.1 Hz, 1H), 6.92 (dd, J=2.3, 0.9 Hz, 1H), 3.53 (s, 3H), 3.46 (q,J=8.8 Hz, 1H), 2.34-2.18 (m, 2H), 2.18-2.04 (m, 2H), 2.04-1.89 (m, 1H),1.89-1.75 (m, 1H), 1.31 (q, J=4.4 Hz, 2H), 1.05 (q, J=4.5 Hz, 2H). MS(APCI) m/z 427.1 (M+H)⁺.

Example I-201-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide

Example 1-20 was prepared using the general procedure described inExample I-11, substituting 1-methyl-1H-indole-7-sulfonamide for1,2,3,4-tetrahydroquinoline-5-sulfonamide and Example I-3C for ExampleI-1D. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm7.98-7.87 (m, 2H), 7.79 (dd, J=7.7, 1.2 Hz, 1H), 7.49 (d, J=2.2 Hz, 1H),7.42 (d, J=3.2 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 6.68 (d, J=3.2 Hz, 1H),3.90 (s, 3H), 3.56-3.39 (m, 4H), 2.35-2.19 (m, 2H), 2.19-2.05 (m, 2H),2.05-1.90 (m, 1H), 1.90-1.75 (m, 1H), 1.38 (q, J=4.4 Hz, 2H), 1.07 (q,J=4.5 Hz, 2H). MS (APCI) 440.1 m/z (M+H)⁺.

Example I-211-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

1H-Indole-4-sulfonamide (21.8 mg, 0.11 mmol, 1.1 eq) was weighed into 4mL vial. Example I-3C (25 mg, 0.10 mmol, 1.0 eq),4-dimethylaminopyridine (13.6 mg, 0.11 mmol, 1.1 eq) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (38.4 mg, 0.20 mmol,2.0 eq) were all combined and dissolved in 0.5 mL dichloromethane. Thestock solution was added to the 4 mL vial containing1H-indole-4-sulfonamide. The reaction was stirred overnight at ambienttemperature. The solvent was removed under a stream of nitrogen, and theresidue was dissolved in dimethyl sulfoxide/methanol. The mixture waspurified via preparative reverse phase HPLC/MS method trifluoroaceticacid 7 to provide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 7.90 (d, J=2.3 Hz, 1H), 7.73 (d, J=8.1Hz, 1H), 7.62-7.54 (m, 2H), 7.39 (d, J=2.4 Hz, 1H), 7.25 (t, J=7.8 Hz,1H), 6.79 (dd, J=3.1, 0.9 Hz, 1H), 3.56 (s, 3H), 3.44 (q, J=8.8 Hz, 1H),2.31-2.19 (m, 2H), 2.16-1.87 (m, 3H), 1.86-1.75 (m, 1H), 1.28 (q, J=4.4Hz, 2H), 1.02-0.97 (m, 2H). MS (APCI) m/z 426.1 (M+H)⁺.

Example I-22N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]cyclopropane-1-carboxamide

Example 1-22 was prepared using the general procedure described inExample I-21, substituting1-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)cyclopropane-1-carboxylicacid from Example I-8A for Example I-3C. ¹H NMR (500 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 11.62 (s, 1H), 8.50-8.45 (m, 1H),7.83-7.78 (m, 1H), 7.74 (dt, J=8.1, 1.0 Hz, 1H), 7.61-7.54 (m, 2H),7.29-7.22 (m, 1H), 6.72 (dd, J=3.1, 0.9 Hz, 1H), 3.59 (s, 3H), 1.29 (q,J=4.4 Hz, 2H), 1.07 (q, J=4.5 Hz, 2H). MS (APCI) m/z 440.0 (M+H)⁺.

Example I-231-(5-cyclobutyl-2-methoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclobutane-1-carboxamide

Example 1-23 was prepared as described in Example I-30D, substitutingExample I-26B for1-(2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylicacid, and pyrazolo[1,5-a]pyridine-4-sulfonamide fornaphthalene-1-sulfonamide. ¹H NMR (500 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.19 (s, 1H), 8.00 (dd, J=8.0, 1.1 Hz,1H), 7.92 (dd, J=7.8, 1.1 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.29 (d,J=2.2 Hz, 1H), 7.14 (ddd, J=8.3, 2.2, 0.7 Hz, 1H), 6.55 (d, J=8.4 Hz,1H), 3.62-3.45 (m, 1H), 3.42 (s, 3H), 2.74 (s, 3H), 2.61-2.48 (m, 2H),2.37-2.07 (m, 6H), 2.06-1.90 (m, 1H), 1.90-1.69 (m, 3H). MS (APCI) m/z440.1 (M+H)⁺.

Example I-241-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-benzimidazole-7-sulfonyl)cyclobutane-1-carboxamide

Example 1-24 was prepared as described in Example I-30D, substitutingExample I-26B for1-(2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylicacid, and 1-methyl-1H-benzo[d]imidazole-7-sulfonamide fornaphthalene-1-sulfonamide. ¹H NMR (500 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.18 (s, 1H), 8.02-7.96 (m, 1H), 7.91(dd, J=7.8, 1.1 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.32-7.23 (m, 1H),7.19-7.07 (m, 1H), 6.55 (d, J=8.4 Hz, 1H), 3.51 (t, J=8.9 Hz, 1H), 3.42(s, 3H), 2.74 (s, 3H), 2.59-2.49 (m, 2H), 2.35-2.26 (m, 2H), 2.22-2.11(m, 4H), 2.05-1.90 (m, 1H), 1.90-1.69 (m, 3H). MS (APCI) m/z 454.0(M+H)⁺.

Example I-251-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclobutane-1-carboxamide

Example 1-25 was prepared as described in Example I-30D, substitutingExample I-26B for1-(2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylicacid, and 1-methyl-1H-indazole-7-sulfonamide fornaphthalene-1-sulfonamide. ¹H NMR (500 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.26 (s, 1H), 8.21-8.13 (m, 1H), 8.10(dd, J=7.5, 1.1 Hz, 1H), 7.34 (t, J=7.7 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H),7.16-7.07 (m, 1H), 6.57 (d, J=8.4 Hz, 1H), 3.67 (s, 3H), 3.51 (p, J=8.8Hz, 1H), 2.72 (s, 3H), 2.59-2.49 (m, 2H), 2.35-2.08 (m, 6H), 2.05-1.91(m, 1H), 1.87-1.70 (m, 3H). MS (APCI) m/z 454.0 (M+H)⁺.

Example I-261-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclobutane-1-carboxamideExample I-26A 1-(5-bromo-2-methoxyphenyl)cyclobutanecarboxylic acid

To 1-(2-methoxyphenyl)cyclobutanecarboxylic acid [CAS #74205-38-2](920mg, 4.46 mmol) in dichloromethane (20 mL) was added N-bromosuccinimide(873 mg, 4.91 mmol). The mixture was stirred at ambient temperature for16 hours. Saturated aqueous Na₂S₂O₃ was added and the organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated. Theresidue was purified via chromatography on a 24 g silica gel cartridge,eluting with methanol in ethyl acetate (0-10% at gradient) to providethe title compound. MS (APCI+) m/z 241 (M-COOH)⁺.

Example I-26B 1-(5-cyclobutyl-2-methoxyphenyl)cyclobutane-1-carboxylicAcid

A mixture of Example I-26A (200 mg, 0.701 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)₂, 57 mg) in tetrahydrofuran (5 mL) was degassed by bubblinga stream of nitrogen through the suspension. Cyclobutylzinc(II) bromide(1 mL, 0.5 M in tetrahydrofuran) was added. The mixture was stirred atambient temperature for 16 hours. The solvent was removed and theresidue was purified via chromatography, eluting with ethylacetate/methanol (9:1) in heptane at a 0-60% gradient to provide thetitle compound. MS (APCI+) m/z 215 (M-COOH)⁺.

Example I-26C 1H-indazole-4-sulfinate

An 20 mL microwave vial was charged with 4-bromo-1H-indazole (500 mg,2.54 mmol), 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (610mg, 2.54 mmol), and PdCl₂(AmPhos)₂(bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),90 mg, 0.127 mmol). A mixture of N-cyclohexyl-N-methylcyclohexanamine(1.640 mL, 7.61 mmol) in anhydrous isopropyl alcohol (IPA) (10 mL) wasadded. The vial was sealed with a Teflon cap, sparged for 5 minutes withnitrogen and subject to microwave conditions at 110° C. for 2.5 hours.After cooling to ambient temperature, the mixture was filtered to givethe crude title product solution. LC/MS (ESI+) m/z 183.1 (M+H)⁺.

Example I-26D 1H-indazole-4-sulfonamide

To a solution of crude 1H-indazole-4-sulfinate (1 g, 5.52 mmol) inisopropyl alcohol (20 mL), water (40 mL) was added. After sodium acetatetrihydrate (2.253 g, 16.56 mmol) and (aminooxy)sulfonic acid (1.872 g,16.56 mmol) were added, the mixture was stirred at ambient temperaturefor 3 hours. The organic solvent was removed under reduced pressure toprovide the crude product which was purified by CombiFlash®chromatography (H₂O (0.01% trifluoroacetic acid) (A)/methanol (B),gradient from 5%-30% of B at 10 minutes-20 minutes to provide the titlecompound and it was used without further purification.

Example I-26E1-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclobutane-1-carboxamide

The title compound was prepared as described in Example I-30D,substituting Example I-26B for1-(2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylicacid, and 1H-indazole-4-sulfonamide for naphthalene-1-sulfonamide. ¹HNMR (500 MHz, dimethyl sulfoxide-d₆) δ ppm 11.58 (t, J=2.3 Hz, 1H), 7.72(dt, J=8.1, 0.9 Hz, 1H), 7.59 (dd, J=7.5, 0.9 Hz, 1H), 7.54-7.46 (m,1H), 7.25 (dd, J=8.1, 7.5 Hz, 1H), 7.17-7.10 (m, 2H), 6.80 (d, J=8.3 Hz,1H), 6.74-6.67 (m, 1H), 3.45 (p, J=8.6 Hz, 1H), 3.38 (s, 3H), 2.46-2.37(m, 2H), 2.32-2.21 (m, 2H), 2.17-2.04 (m, 4H), 2.02-1.88 (m, 1H),1.86-1.72 (m, 1H), 1.70-1.58 (m, 1H), 1.58-1.47 (m, 1H). MS (APCI) m/z439.1 (M+H)⁺.

Example I-271-(5-cyclopropyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide

Example 1-27 was prepared as described in Example 1-16, substituting1-(5-bromo-2-methoxyphenyl)-N-((1,2,3,4-tetrahydroquinolin-5-yl)sulfonyl)cyclobutane-1-carboxamidefrom Example 1-9 for Example 11, and cyclopropylzinc bromide forcyclobutylzinc bromide. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1(v/v)) δ ppm 7.14-6.98 (m, 3H), 6.95 (dd, J=8.5, 2.2 Hz, 1H), 6.85 (d,J=8.4 Hz, 1H), 6.69 (dd, J=7.9, 1.5 Hz, 1H), 3.51 (s, 3H), 3.06 (t,J=5.5 Hz, 2H), 2.64-2.48 (m, 4H), 2.43-2.01 (m, 2H), 1.98-1.83 (m, 1H),1.83-1.67 (m, 2H), 1.67-1.50 (m, 2H), 0.99-0.82 (m, 2H), 0.74-0.56 (m,2H). MS (APCI) m/z 441.1 (M+H)⁺.

Example I-281-(2,5-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamideExample I-28A Methyl 1-(2,5-dimethoxyphenyl)cyclopropanecarboxylate

To a mixture of bis(dibenzylideneacetone)palladium (81 mg, 0.14 mmol)and Q-Phos (1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene)(100 mg, 0.14 mmol) in anhydrous tetrahydrofuran (30 mL) was added2-bromo-1,4-dimethoxybenzene (1.05 mL, 7.0 mmol) followed by ˜0.4 M(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide in tetrahydrofuran (21mL, ˜8.4 mmol) and the reaction was stirred at ambient temperature for16 hours. The reaction was quenched with 1 M aqueous citric acid (7 mL)and diluted with brine (7 mL) and heptane (15 mL). The aqueous phase wasseparated and extracted with methyl tert-butyl ether. The combinedorganic phases were dried (Na₂SO₄), concentrated and the residue waschromatographed on silica (15 to 20% methyl tert-butyl ether/heptanes)to provide the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 6.81-6.76(m, 3H), 3.79 (s, 3H), 3.76 (s, 3H), 3.61 (s, 3H), 1.60-1.57 (m, 2H),1.12-1.09 (m, 2H). MS (DCI) m/z 254 (M+NH₄).

Example I-28B 1-(2,5-dimethoxyphenyl)cyclopropanecarboxylic Acid

Methyl 1-(2,5-dimethoxyphenyl)cyclopropanecarboxylate (473 mg, 2.00mmol) from example I-28A was placed in isopropanol (12 mL), treated with3 M aqueous NaOH (4 mL) and heated at 55° C. for 15 hours. The reactionwas reduced in volume and acidified with 1 M aqueous citric acid (10mL). The resulting suspension was extracted with methyl tert-butyl etherand the combined extracts were washed twice with water, and each washwas back-extracted once with methyl tert-butyl ether. The organics weredried (Na₂SO₄) and concentrated to provide the title compound. ¹H NMR(500 MHz, dimethyl sulfoxide-d₆) δ ppm 11.98 (bs, 1H), 6.87 (d, J=8.8Hz, 1H), 6.78 (dd, J=8.8, 3.1 Hz, 1H), 6.74 (d, J=3.1 Hz, 1H), 3.71 (s,3H), 3.69 (s, 3H), 1.40-1.37 (m, 2H), 1.04-1.00 (m, 2H). MS (ESI−) m/z221 (M−H)⁻.

Example I-28C1-(2,5-dimethoxyphenyl)-N-(naphthalen-1-ylsulfonyl)cyclopropanecarboxamide

To a mixture of 1-(2,5-dimethoxyphenyl)cyclopropanecarboxylic acid (89mg, 0.4 mmol) from Example I-28B, EDAC(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl, 153 mg, 0.80 mmol)and 4-dimethylaminopyridine (54 mg, 0.44 mmol) in anhydrousdichloromethane (1.5 mL) was added naphthalene-1-sulfonamide (104 mg,0.50 mmol). The solution was stirred at ambient temperature for 16hours, concentrated and purified by reverse-phase HPLC [Waters XBridge™C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 70%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid] to givethe title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.46(s, 1H), 8.58-8.53 (m, 1H), 8.30-8.22 (m, 2H), 8.13-8.08 (m, 1H),7.71-7.65 (m, 3H), 6.82 (dd, J=8.9, 2.9 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H),6.70 (d, J=2.9 Hz, 1H), 3.70 (s, 3H), 3.28 (s, 3H), 1.25-1.20 (m, 2H),0.98-0.92 (m, 2H). MS (ESI) m/z 412 (M+H)⁻.

Example I-291-(2,5-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of 1-(2,5-dimethoxyphenyl)cyclopropanecarboxylic acid (23 mg,0.10 mmol) from Example I-28B, quinoline-5-sulfonamide (25 mg, 0.12mmol), EDAC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl, 38 mg,0.20 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol) was dilutedwith anhydrous N,N-dimethylacetamide (400 μL), stirred at ambienttemperature for 16 hours and then purified by reverse-phase HPLC [WatersXBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 10 to50% gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid] togive the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm11.60 (bs, 1H), 9.06 (dd, J=4.2, 1.6 Hz, 1H), 9.00-8.96 (m, 1H), 8.35(dd, J=8.5, 1.2 Hz, 1H), 8.32 (dd, J=7.5, 1.2 Hz, 1H), 7.95 (dd, J=8.5,7.5 Hz, 1H), 7.71 (dd, J=8.8, 4.2 Hz, 1H), 6.83 (dd, J=8.8, 2.9 Hz, 1H),6.78 (d, J=8.8 Hz, 1H), 6.71 (d, J=2.9 Hz, 1H), 3.71 (s, 3H), 3.29 (s,3H), 1.24-1.20 (m, 2H), 0.98-0.94 (m, 2H). MS (ESI+) m/z 413 (M+H)+.

Example I-301-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamideExample I-30A 3-bromo-N,N-dimethyl-5-(trifluoromethyl)pyridin-2-amine

To a solution of 3-bromo-2-chloro-5-(trifluoromethyl)pyridine (1.575 g,6.05 mmol) in tetrahydrofuran (3 mL) was added 3 mL of a 40% aqueoussolution of dimethylamine (1.704 g, 15.12 mmol). The mixture becamecloudy and initially cooled down but then warmed up slightly, to about35° C. The reaction mixture was stirred at ambient temperature for 1hour. The aqueous layer was extracted with hexanes (3×5 mL) and theextracts were filtered through a very small silica gel plug. The solventwas blown off under a stream of nitrogen to provide the title compound.¹H NMR (501 MHz, chloroform-d) δ ppm 8.40 (dq, J=2.0, 0.9 Hz, 1H),8.01-7.81 (m, 1H), 3.14 (s, 6H). MS (APCI+) m/z 269 (M+H)⁺.

Example I-30B methyl1-(2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylate

In a 4 mL vial was added Pd₂(dba)₃(tris(dibenzylideneacetone)dipalladium(0)) (6.53 mg, 7.14 mol) andQ-Phos (1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene)(1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (5.07 mg,7.14 μmol) in tetrahydrofuran (tetrahydrofuran) (0.5 mL).3-Bromo-N,N-dimethyl-5-(trifluoromethyl)pyridin-2-amine (Example I-30A,96 mg, 0.357 mmol) in tetrahydrofuran (0.500 mL) was added.(1-(Methoxycarbonyl)cyclopropyl)zinc(II) bromide (0.741 mL, 0.392 mmol)was added and the reaction mixture was stirred at ambient temperaturefor 16 hours. The reaction mixture was poured into 5 mL saturatedaqueous NH₄Cl and was extracted with 2×5 mL methyl tert-butyl ether. Theorganic layer was concentrated in vacuo and was carried on to the nextstep.

Example I-30C1-(2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylicAcid

In a 20 mL vial, methyl1-(2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylate(Example I-30B, 536 mg, 1.858 mmol) was dissolved in 10 mL 3:2tetrahydrofuran:methanol. Lithium hydroxide (5 M aqueous solution, 1.858mL, 9.29 mmol) was added and the reaction was stirred for 16 hours at45° C. The sample was concentrated in vacuo, and was acidified with 2 Maqueous HCl. The material was purified directly via reverse phase HPLCon a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×21.2 mm). Agradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B)was used, at a flow rate of 2-40 mL/minute from 0-0.5 minute with 5% A,flow rate of 40 mL/minute from 0.5-4.9 minute with a linear gradient5-100% A, and flow rate from 40-2 mL/minute from 4.9-5.0 minutes, toobtain title compound.

Example I-30D1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

Into a 4 mL vial was added1-(2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl)cyclopropanecarboxylicacid (Example I-30C, 64 mg, 0.233 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (89 mg, 0.467 mmol), and N,N-dimethylpyridin-4-amine (31.4mg, 0.257 mmol) in dichloromethane (2 mL). Naphthalene-1-sulfonamide(53.2 mg, 0.257 mmol) was added. The reaction was stirred for 16 hoursat ambient temperature. The solvent was removed under nitrogen. Theresidue was dissolved in methanol and the mixture was purified usingpreparative reverse phase HPLP/MS method trifluoroacetic acid 1 toprovide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δppm 8.64-8.46 (m, 1H), 8.35 (dd, J=2.4, 1.1 Hz, 1H), 8.31-8.19 (m, 2H),8.19-8.05 (m, 1H), 7.75-7.65 (m, 3H), 7.61 (d, J=2.4 Hz, 1H), 2.64 (s,6H), 1.48 (q, J=4.4 Hz, 2H), 1.15 (q, J=4.3 Hz, 2H). MS (APCI) m/z 464.0(M+H)⁺.

Example I-311-(5-ethoxy-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-31A Ethyl 2-(2-methoxyphenyl)acrylate

A solution of ethyl pyruvate (4.47 mL, 40.0 mmol) in tetrahydrofuran (40mL) at 0° C. was treated dropwise with 1 M 2-methoxyphenylmagnesiumbromide in tetrahydrofuran (20 mL, 20.00 mmol) at 0° C. The mixture wasstirred at ambient temperature for 30 minutes and quenched withsaturated aqueous NH₄Cl solution (20 mL). The mixture was concentratedto remove the majority of the tetrahydrofuran. The residue was extractedwith methyl tert-butyl ether (2×50 mL). The combined methyl tert-butylether layers were washed with brine, dried (MgSO₄), filtered, andconcentrated. The residue was taken up in toluene (50 mL), treated withp-toluenesulfonic acid monohydrate (3.80 g, 20.00 mmol), and, using aDean-Starke trap, heated to 120° C. for 1 hour, and then further heatedto 140° C. for 30 minutes. The mixture was cooled and partitionedbetween methyl tert-butyl ether (˜50 mL) and saturated aqueous NaHCO₃solution (25 mL). The organic layer was washed with brine, dried(MgSO₄), filtered, concentrated, and chromatographed on silica gel,eluting with a gradient of 5% to 50% ethyl acetate in heptanes toprovide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.33 (ddd,J=1.8, 7.5, 8.3 Hz, 1H), 7.23 (dd, J=1.7, 7.4 Hz, 1H), 6.96 (td, J=1.1,7.4 Hz, 1H), 6.89 (dd, J=1.0, 8.3 Hz, 1H), 6.27 (d, J=1.6 Hz, 1H), 5.73(d, J=1.6 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 1.27 (t, J=7.1Hz, 3H).

Example I-31B Ethyl 1-(2-methoxyphenyl)cyclopropane-1-carboxylate

A solution of trimethylsulfoxonium iodide (4.05 g, 18.41 mmol) indimethylsulfoxide (20 mL) was treated with potassium tert-butoxide(2.065 g, 18.41 mmol), and stirred at ambient temperature for 45minutes. The mixture was treated with a solution of Example I-31A (ethyl2-(2-methoxyphenyl)acrylate) (2.92 g, 14.16 mmol) in toluene (20 mL),stirred at ambient temperature for 50° C. for 1 hour, cooled to 0° C.,and partitioned between methyl tert-butyl ether (100 mL) and 1 M aqueousHCl (50 mL). The layers were separated and the aqueous layer wasextracted with methyl tert-butyl ether (50 mL). The combined organiclayers were washed with water (30 mL) and washed with brine, dried(MgSO₄), filtered, concentrated, and chromatographed on silica gel,eluting with a gradient of 5% to 50% ethyl acetate in heptanes toprovide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.26 (td,J=1.8, 8.0 Hz, 1H), 7.19 (dd, J=1.7, 7.5 Hz, 1H), 6.90 (td, J=1.2, 7.5Hz, 1H), 6.87 (dd, J=1.1, 8.2 Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.83 (s,3H), 1.59 (q, J=4.1 Hz, 2H), 1.14 (t, J=7.1 Hz, 3H), 1.10 (q, J=4.1 Hz,2H).

Example I-31C Ethyl1-(5-bromo-2-methoxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-31B (ethyl1-(2-methoxyphenyl)cyclopropanecarboxylate) (1.47 g, 6.67 mmol) intetrahydrofuran (25 mL) and water (degassed, 14 mL) was treated withbenzyltrimethylammonium tribromide (2.73 g, 7.01 mmol) and stirred for16 hours at ambient temperature. The tetrahydrofuran was removed on arotavap and the residue was extracted with methyl tert-butyl ether(twice). The combined methyl tert-butyl ether layers were washed withbrine, dried (MgSO₄), filtered through a pad of silica gel, andconcentrated to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δppm 7.34 (dd, J=2.5, 8.6 Hz, 1H), 7.28 (d, J=2.5 Hz, 1H), 6.73 (d, J=8.7Hz, 1H), 4.08 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 1.58 (q, J=4.2 Hz, 2H),1.14 (t, J=7.1 Hz, 3H), 1.08 (q, J=4.2 Hz, 2H). LC/MS (APCI+) m/z 299,301 (M+H)⁺.

Example I-31D Ethyl1-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane-1-carboxylate

A mixture of Example I-31C (ethyl1-(5-bromo-2-methoxyphenyl)cyclopropanecarboxylate) (1.87 g, 6.25 mmol),potassium acetate (3.07 g, 31.3 mmol) and bis(pinacolato)diboron (4.76g, 18.75 mmol) in dioxane (90 mL) was vacuum purged with nitrogenseveral times, treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane, (0.510 g, 0.625 mmol) and heated for 16 hours at100° C. under nitrogen. The mixture was cooled and partitioned betweenmethyl tert-butyl ether (˜75 mL) and 1 M aqueous HCl (15 mL). The layerswere separated and the aqueous layer was extracted with methyltert-butyl ether (˜25 mL). The combined methyl tert-butyl ether layerswere washed with brine, dried (MgSO₄), filtered, concentrated, andchromatographed on silica gel, eluting with a gradient of 5% to 30%[200:1:1 ethyl acetate:HCOOH:H₂O] in heptanes to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.73 (dd, J=1.5, 8.2 Hz, 1H),7.62 (d, J=1.6 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 4.05 (q, J=7.0 Hz, 2H),3.84 (s, 3H), 1.56 (q, J=4.1 Hz, 2H), 1.32 (s, 12H), 1.15-1.09 (m, 5H).

Example I-31E Ethyl1-(5-hydroxy-2-methoxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-31D (ethyl1-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxylate)(0.65 g, 1.877 mmol) in methanol (20 mL) was treated with 30% aqueoushydrogen peroxide solution (1.918 mL, 18.77 mmol). The mixture wasstirred for 16 hours. The mixture was diluted with methyl tert-butylether (100 mL), washed with 0.1 M aqueous HCl (2×100 mL), washed with asolution of sodium thiosulfate pentahydrate (5.13 g, 20.65 mmol) inwater (50 mL), washed with brine, dried (MgSO₄), filtered, andconcentrated to provide title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm6.73-6.67 (m, 3H), 4.97 (s, 1H), 4.09 (q, J=7.0 Hz, 2H), 3.77 (s, 3H),1.59-1.55 (m, 2H), 1.15 (t, J=7.1 Hz, 3H), 1.10-1.06 (m, 2H).

Example I-31F Ethyl1-(5-ethoxy-2-methoxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-31E (ethyl1-(5-hydroxy-2-methoxyphenyl)cyclopropanecarboxylate) (37 mg, 0.157mmol) and iodoethane (41.5 μl, 0.513 mmol) in N,N-dimethylformamide (0.5mL) was treated with 60% dispersion of sodium hydride in mineral oil(18.79 mg, 0.470 mmol), stirred at ambient temperature for 15 minutes,and partitioned between methyl tert-butyl ether (50 mL) and 1 M aqueousHCl (15 mL). The layers were separated and the methyl tert-butyl etherlayer was washed with 0.2 M aqueous HCl (˜10 mL), washed with brine,dried (MgSO₄), filtered, concentrated and chromatographed on silica geleluting with 10% ethyl acetate in heptanes to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 6.78-6.74 (m, 3H), 4.08 (q,J=7.1 Hz, 2H), 3.97 (q, J=7.0 Hz, 2H), 3.78 (s, 3H), 1.58-1.55 (m, 2H),1.38 (t, J=7.0 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H), 1.09 (q, J=4.1 Hz, 2H).

Example I-31G 1-(5-ethoxy-2-methoxyphenyl)cyclopropane-1-carboxylic Acid

A solution of Example 1-31F (ethyl1-(5-ethoxy-2-methoxyphenyl)cyclopropanecarboxylate) (33 mg, 0.125 mmol)in tetrahydrofuran (˜1.5 mL) was diluted with methanol (˜1.5 mL),treated with 3 M aqueous NaOH (˜1 mL), heated to 70° C. for 90 minutes,cooled, and partitioned between methyl tert-butyl ether (40 mL) and 1 Maqueous HCl (10 mL). The methyl tert-butyl ether layer was washed withbrine, dried (MgSO₄), filtered, and concentrated to provide the titlecompound. ¹H NMR (501 MHz, CDCl₃) δ ppm 6.80-6.77 (m, 3H), 3.96 (q,J=7.0 Hz, 2H), 3.79 (s, 3H), 1.63 (q, J=4.1 Hz, 2H), 1.37 (t, J=7.0 Hz,3H), 1.16 (q, J=4.1 Hz, 2H).

Example I-31H1-(5-ethoxy-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of Example I-31G(1-(5-ethoxy-2-methoxyphenyl)cyclopropanecarboxylic acid) (13 mg, 0.055mmol), quinoline-5-sulfonamide (17.19 mg, 0.083 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.10 mg,0.110 mmol) in N,N-dimethylformamide (0.3 mL) was added4-dimethylaminopyridine (13.44 mg, 0.110 mmol). The mixture was stirredfor about 72 hours. The mixture was partitioned between methyltert-butyl ether (50 mL) and 0.2 M aqueous HCl (15 mL). The methyltert-butyl ether layer was washed with 0.2 M aqueous HCl (˜10 mL),washed with brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 25% to 100%[200:1:1 ethyl acetate:HCOOH:H₂O] in heptanes to provide the titlecompound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.60 (s, 1H),9.04 (dd, J=1.6, 4.2 Hz, 1H), 8.97 (dt, J=1.2, 8.7 Hz, 1H), 8.36-8.29(m, 2H), 7.93 (t, J=7.9 Hz, 1H), 7.69 (dd, J=4.2, 8.8 Hz, 1H), 6.81 (dd,J=2.9, 8.9 Hz, 1H), 6.77 (d, J=8.9 Hz, 1H), 6.69 (d, J=2.9 Hz, 1H), 3.96(q, J=6.9 Hz, 2H), 3.29 (s, 3H), 1.30 (t, J=7.0 Hz, 3H), 1.20 (q, J=4.3Hz, 2H), 0.96-0.93 (m, 2H). LC/MS (APCI+) m/z 427 (M+H)⁺.

Example I-321-[5-(cyclobutyloxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-32A 1-(5-cyclobutoxy-2-methoxyphenyl)cyclopropane-1-carboxylicAcid

A solution of Example I-31E (ethyl1-(5-hydroxy-2-methoxyphenyl)cyclopropanecarboxylate) (41 mg, 0.174mmol) and bromocyclobutane (120 mg, 0.889 mmol) in N,N-dimethylformamide(0.5 mL) was treated with 60% dispersion of sodium hydride in mineraloil (30 mg, 0.750 mmol), stirred at ambient temperature for 3 hours,heated to 45° C. for 1 hour, cooled and partitioned between methyltert-butyl ether (50 mL) and 1 M aqueous HCl (15 mL). The methyltert-butyl ether layer wash washed with 0.2 M aqueous HCl (10 mL),washed with brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 10% to 30%ethyl acetate in heptanes to provide the title compound. ¹H NMR (500MHz, CDCl₃) δ ppm 6.76 (d, J=8.8 Hz, 1H), 6.72 (d, J=2.9 Hz, 1H), 6.68(dd, J=3.0, 8.8 Hz, 1H), 4.57-4.51 (m, 1H), 3.79 (s, 3H), 2.44-2.36 (m,2H), 2.18-2.08 (m, 2H), 1.87-1.78 (m, 1H), 1.70-1.58 (m, 3H), 1.15 (t,J=3.6 Hz, 2H).

Example I-32B1-[5-(cyclobutyloxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

A solution of Example I-32A(1-(5-cyclobutoxy-2-methoxyphenyl)cyclopropanecarboxylic acid) (8.6 mg,0.033 mmol), quinoline-5-sulfonamide (10.24 mg, 0.049 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (12.57 mg,0.066 mmol) in N,N-dimethylformamide (0.3 mL) was treated with4-dimethylaminopyridine (8.01 mg, 0.066 mmol) and stirred at ambienttemperature for 16 hours. The mixture was diluted withN,N-dimethylformamide and was directly purified by reverse-phase HPLC[Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute,5-95% gradient of acetonitrile in 0.1% trifluoroacetic acid] to affordthe title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.60(s, 1H), 9.05 (dd, J=1.6, 4.2 Hz, 1H), 8.98 (dt, J=1.1, 8.9 Hz, 1H),8.35 (d, J=8.5 Hz, 1H), 8.31 (dd, J=1.2, 7.5 Hz, 1H), 7.94 (dd, J=7.6,8.3 Hz, 1H), 7.70 (dd, J=4.2, 8.8 Hz, 1H), 6.75 (d, J=8.9 Hz, 1H), 6.71(dd, J=2.9, 8.8 Hz, 1H), 6.61 (d, J=2.8 Hz, 1H), 4.59 (p, J=7.2 Hz, 1H),3.29 (s, 3H), 2.43-2.34 (m, 2H), 2.06-1.95 (m, 2H), 1.81-1.71 (m, 1H),1.68-1.56 (m, 1H), 1.21 (q, J=4.3 Hz, 2H), 0.94 (q, J=4.4 Hz, 2H). LC/MS(APCI+) m/z 453 (M+H)⁺.

Example I-331-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclobutane-1-carboxamide

A mixture of Example I-26B (60 mg, 0.230 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (71.6 mg,0.461 mmol) and N,N-dimethylpyridin-4-amine (56.3 mg, 0.461 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. 2-Methylquinoline-5-sulfonamide (56.3 mg, 0.254 mmol) wasadded. The mixture was stirred at 45° C. for 3 hours. The solvent wasremoved and the residue was dissolved in methanol (3 mL) and filtered.Purification via HPLC with the trifluoroacetic acid method provided thetitle compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.49 (s,1H), 8.58 (d, J=8.8 Hz, 1H), 8.29-8.16 (m, 2H), 7.88 (dd, J=8.4, 7.5 Hz,1H), 7.37 (d, J=8.9 Hz, 1H), 7.21 (d, J=2.2 Hz, 1H), 7.09 (dd, J=8.4,2.2 Hz, 1H), 6.59 (d, J=8.3 Hz, 1H), 3.51 (q, J=8.8 Hz, 1H), 3.17 (s,1H), 3.12 (s, 3H), 2.69 (s, 3H), 2.45-2.35 (m, 2H), 2.31 (dtt, J=10.6,7.5, 2.5 Hz, 2H), 2.22-2.06 (m, 4H), 2.04-1.92 (m, 1H), 1.90-1.77 (m,1H), 1.73-1.50 (m, 2H). MS (ESI+) m/z 465 (M+H)⁺.

Example I-341-(5-tert-butyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-34A 1-(5-(tert-butyl)-2-methoxyphenyl)cyclopropanecarboxylicAcid

The title compound was prepared as described in Example I-30B to ExampleI-30C, substituting 2-bromo-4-(tert-butyl)-1-methoxybenzene for ExampleI-30A.

Example I-34B1-(5-tert-butyl-2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Quinoline-5-sulfonamide (24.9 mg, 0.10 mmol, 1.2 eq) was weighed into a4 mL vial and dichloromethane (0.2 mL) was added.1-(5-(tert-Butyl)-2-methoxyphenyl)cyclopropanecarboxylic acid (24.8 mg,0.12 mmol, 1.0 eq) from Example I-34A was mixed with a solution of1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (38.0 mg,0.2 mmol, 2.0 eq) and 4-dimethylaminopyridine (13.4 mg, 0.11 mmol, 1.1eq) in dichloromethane (0.5 mL). The stock solution was combined withthe sulfonamide and the mixture was stirred for 16 hours at ambienttemperature. The solvent was removed under a stream of nitrogen. Theresidue was dissolved in 1:1 dimethyl sulfoxide/methanol and purifiedvia preparative reverse phase HPLC/MS method trifluoroacetic acid 7 toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 9.06 (dd, J=4.2, 1.6 Hz, 1H), 9.01-8.94 (m, 1H), 8.36 (dt, J=8.4,1.1 Hz, 1H), 8.32 (dd, J=7.5, 1.2 Hz, 1H), 7.96 (dd, J=8.5, 7.5 Hz, 1H),7.73 (dd, J=8.8, 4.2 Hz, 1H), 7.26 (dd, J=8.6, 2.5 Hz, 1H), 7.08 (d,J=2.5 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 3.31 (s, 3H), 1.28 (q, J=4.4 Hz,2H), 1.23 (s, 9H), 0.97 (q, J=4.6 Hz, 2H). MS (APCI) m/z 439.1 (M+H)⁺.

Example I-351-[2-methoxy-5-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-35A 1-(5-isopropyl-2-methoxyphenyl)cyclopropanecarboxylic Acid

The title compound was prepared as described in the procedure describedfrom Example 1-30B to Example I-30C, substituting2-bromo-4-isopropyl-1-methoxybenzene for Example I-30A.

Example I-35B1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Quinoline-5-sulfonamide (24.9 mg, 0.12 mmol, 1.2 eq) was weighed into a4 mL vial and dichloromethane (0.2 mL) was added.1-(5-(Isopropyl)-2-methoxyphenyl)cyclopropanecarboxylic acid (23.4 mg,0.12 mmol, 1.0 eq) from Example 35A was mixed with a solution of1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (38.0 mg,0.2 mmol, 2.0 eq) and 4-dimethylaminopyridine (13.4 mg, 0.11 mmol, 1.1eq) in dichloromethane (0.5 mL). The stock solution was combined withthe sulfonamide and the mixture was stirred for 16 hours at ambienttemperature. The solvent was removed under a stream of nitrogen. Theresidue was dissolved in dimethyl sulfoxide/methanol (1:1) and purifiedvia preparative reverse phase HPLC/MS method trifluoroacetic acid 7 toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.98 (dt, J=8.8, 1.3 Hz, 1H), 8.36(dt, J=8.5, 1.1 Hz, 1H), 8.33 (dd, J=7.5, 1.2 Hz, 1H), 7.96 (dd, J=8.4,7.5 Hz, 1H), 7.74 (dd, J=8.8, 4.2 Hz, 1H), 7.12 (dd, J=8.4, 2.3 Hz, 1H),6.95 (d, J=2.3 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 3.30 (s, 3H), 2.80 (p,J=6.9 Hz, 1H), 1.26 (q, J=4.4 Hz, 2H), 1.15 (d, J=6.9 Hz, 6H), 0.96 (q,J=4.5 Hz, 2H). MS (APCI) m/z 425.1 (M+H)⁺.

Example I-361-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example 1-36 was prepared as described in Example I-34B, substituting1-(4-fluoro-5-isopropyl-2-methoxyphenyl)cyclopropane-1-carboxylic acidfor Example I-34A. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v))δ ppm 9.07 (dd, J=4.2, 1.6 Hz, 1H), 8.96 (dt, J=8.8, 1.3 Hz, 1H),8.42-8.27 (m, 2H), 7.97 (dd, J=8.5, 7.5 Hz, 1H), 7.74 (dd, J=8.8, 4.2Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 6.68 (d, J=12.6 Hz, 1H), 3.32 (s, 3H),3.06 (p, J=7.0 Hz, 1H), 1.28 (q, J=4.3 Hz, 2H), 1.20 (d, J=6.9 Hz, 6H),0.97 (q, J=4.5 Hz, 2H). MS (APCI) m/z 443.0 (M+H)⁺.

Example I-371-[2-methoxy-5-(trifluoromethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-37A1-(2-methoxy-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic Acid

The title compound was prepared as described in Example I-30B to ExampleI-30C, substituting 2-bromo-1-methoxy-4-(trifluoromethyl)benzene [CAS#402-10-8] for Example 1-30A.

Example I-37B1-[2-methoxy-5-(trifluoromethyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example I-37B was prepared as described in Example I-34B, substituting1-(2-methoxy-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxylic acidfrom Example I-37A for Example I-34A. ¹H NMR (400 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.91(dt, J=8.8, 1.3 Hz, 1H), 8.40-8.29 (m, 2H), 7.96 (dd, J=8.5, 7.5 Hz,1H), 7.72 (dd, J=8.8, 4.2 Hz, 1H), 7.64 (dd, J=8.8, 2.3 Hz, 1H), 7.42(d, J=2.3 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 3.34 (s, 3H), 1.29 (q, J=4.5Hz, 2H), 1.02 (q, J=4.6 Hz, 2H). MS (APCI) m/z 451.0 (M+H)⁺.

Example I-381-[5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-38A 1-(3-bromo-4-methoxyphenyl)bicyclo[1.1.1]pentane

A solution of 4-(bicyclo[1.1.1]pentan-1-yl)phenol (0.511 g, 3.19 mmol)and benzyltrimethylammonium tribromide (1.244 g, 3.19 mmol) intetrahydrofuran (9) and degassed water (6.00 mL) was stirred at ambienttemperature overnight. The volatiles were reduced in volume and theresulting mixture was diluted with 500 mL of methyl tert-butyl ether.The organics were washed with brine, dried (Na₂SO₄), filtered through apad of cotton and concentrated to give4-(bicyclo[1.1.1]pentan-1-yl)-2-bromophenol. The4-(bicyclo[1.1.1]pentan-1-yl)-2-bromophenol was treated with potassiumcarbonate (0.662 g, 4.79 mmol), and dimethyl sulfate (0.453 mL, 4.79mmol) in acetone (15.96 mL) and stirred at ambient temperature for 3hours. The reaction mixture was quenched withN-ethyl-N-isopropylpropan-2-amine (1.0 mL, 5.73 mmol) and the solventwas removed. The mixture was diluted with water and the organicsseparated, concentrated, and purified using a 10 g silica gel cartridgewith a gradient of 1-100% ethyl acetate/heptanes over 20 minutes toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.38(d, J=2.1 Hz, 1H), 7.10 (dd, J=8.3, 2.1 Hz, 1H), 6.83 (d, J=8.3 Hz, 1H),3.88 (s, 3H), 2.54 (s, 1H), 2.05 (s, 6H).

Example I-38B1-(5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl)cyclopropanecarboxylicAcid

The title compound was prepared as described in the procedure describedfrom Example I-30B to Example I-30C, substituting1-(3-bromo-4-methoxyphenyl)bicyclo[1.1.1]pentane from Example I-38A forExample I-30A.

Example I-38C1-[5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Quinoline-5-sulfonamide (24.9 mg, 0.12 mmol, 1.2 eq) was weighed into 4mL vials and dichloromethane (0.2 mL) was added.1-(5-(Bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl)cyclopropanecarboxylicacid (25.8 mg, 0.12 mmol, 1.0 eq) from Example I-38B was mixed with asolution of 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride (38.0 mg, 0.2 mmol, 2.0 eq) and DMAP(4-dimethylaminopyridine, 13.4 mg, 0.11 mmol, 1.1 eq) in dichloromethane(0.5 mL). The stock solution was combined with the sulfonamide and themixture was stirred for 16 hours at ambient temperature. The solvent wasremoved under a stream of nitrogen. The residue was dissolved indimethyl sulfoxide/methanol and purified via preparative reverse phaseHPLC/MS method trifluoroacetic acid 7 to afford the title compound. ¹HNMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 9.05 (dd, J=4.2, 1.6 Hz, 1H),8.97 (dt, J=8.9, 1.2 Hz, 1H), 8.39-8.28 (m, 2H), 7.95 (dd, J=8.4, 7.5Hz, 1H), 7.73 (dd, J=8.8, 4.2 Hz, 1H), 7.08 (dd, J=8.3, 2.1 Hz, 1H),6.91 (d, J=2.1 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.30 (s, 3H), 2.49 (s,1H), 1.99 (s, 6H), 1.25 (q, J=4.4 Hz, 2H), 0.95 (q, J=4.5 Hz, 2H). MS(APCI) m/z 449.0 (M+H)⁺.

Example I-391-(5-tert-butyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example 1-39 was prepared as described in Example I-34B, substituting1,2,3,4-tetrahydroquinoline-5-sulfonamide acid forquinoline-5-sulfonamide. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1(v/v)) δ ppm 7.32 (dd, J=8.6, 2.5 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H),7.11-6.98 (m, 2H), 6.93 (d, J=8.6 Hz, 1H), 6.72 (dd, J=6.9, 2.6 Hz, 1H),3.71 (s, 3H), 3.23-3.12 (m, 2H), 2.84 (t, J=6.4 Hz, 2H), 1.76 (p, J=6.2Hz, 2H), 1.40 (q, J=4.3 Hz, 2H), 1.26 (s, 9H), 1.14-0.95 (m, 2H). MS(APCI) m/z 443.1 (M+H)⁺.

Example I-401-(2,6-dimethoxy-3-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamideExample I-40A 3-bromo-2,4-dimethoxybenzaldehyde

2-Bromo-1,3-dimethoxybenzene (2.22 g, 10.2 mmol) dissolved intoanhydrous dichloromethane (25 mL), chilled near −40° C. and treated overa few minutes with 1 M TiCl₄ in dichloromethane (15.3 mL, 15.3 mmol)followed several minutes later with dichloro(methoxy)methane (1.0 mL,11.1 mmol). The reaction mixture and Dewer flask were covered withinsulation, allowed to warm slowly to ambient temperature for 16 hoursand then poured over ice. The product was extracted into dichloromethaneand the combined extracts were dried (Na₂SO₄), concentrated andchromatographed on silica (20 to 40% methyl tert-butyl ether/heptane) togive the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 10.23 (d, J=0.8Hz, 1H), 7.85 (d, J=8.8 Hz, 1H), 6.82 (dd, J=8.8, 0.8 Hz, 1H), 3.99 (s,3H), 3.99 (s, 3H). MS (DCI) m/z 245/247 (M+H)⁺.

Example I-40B 2-bromo-1,3-dimethoxy-4-methylbenzene

To trifluoroacetic acid (15 mL) stirred at −15° C. was added3-bromo-2,4-dimethoxybenzaldehyde (980 mg, 4.0 mmol) from Example I-40Afollowed immediately by triethylsilane (3.2 mL, 20 mmol). The reactionmixture was stirred cold for six minutes, concentrated under vacuum,filtered through silica with chloroform/heptane, reconcentrated andchromatographed through silica (10 to 30% chloroform/heptane) to givethe title compound. ¹HNMR (501 MHz, CDCl₃) δ ppm 7.06 (dq, J=8.4, 0.75Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 2.27 (d,J=0.75 Hz, 3H). MS (APCI) m/z 231/233 (M+H)+.

Example I-40C methyl1-(2,6-dimethoxy-3-methylphenyl)cyclopropanecarboxylate

To bis(dibenzylideneacetone)palladium (29 mg, 0.050 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (36 mg,0.051 mmol) under nitrogen was added a solution of2-bromo-1,3-dimethoxy-4-methylbenzene (578 mg, 2.50 mmol) from ExampleI-40B in anhydrous tetrahydrofuran (10 mL) followed by −0.4 M(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide in tetrahydrofuran(12.5 mL, −5 mmol) and the reaction was stirred at ambient temperaturefor 16 hours. The reaction was quenched with 1 M aqueous citric acid (4mL) and diluted with brine (4 mL) and heptane (10 mL). The aqueous phasewas separated and extracted with methyl tert-butyl ether and thecombined organic phases were dried (Na₂SO₄), concentrated andchromatographed on silica (15 to 20% methyl tert-butyl ether/heptanes)to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.06 (dq,J=8.4, 0.8 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H),3.62 (s, 3H), 2.20 (d, J=0.8 Hz, 3H), 1.72-1.68 (m, 2H), 1.26-1.22 (m,2H). MS (DCI) m/z=268 (M+NH₄)+.

Example I-40D 1-(2,6-dimethoxy-3-methylphenyl)cyclopropanecarboxylicAcid

Methyl 1-(2,6-dimethoxy-3-methylphenyl)cyclopropanecarboxylate (0.57 g,2.28 mmol) from Example I-40C was placed in isopropanol (15 mL) within aHDPE (high density polyethylene) bottle, treated with 3 M aqueous NaOH(5 mL) and heated one day at 70° C. More 3 M aqueous NaOH (2 mL) wasadded and the reaction mixture was heated in a glass microwave vial at140° C. for 80 minutes, brought toward ambient temperature, partiallyconcentrated and acidified with 1 M aqueous citric acid (15 mL). Thedesired product was extracted with methyl tert-butyl ether and thecombined extracts were washed twice with water. The first wash wasback-extracted once with methyl tert-butyl ether, dried (Na₂SO₄) andconcentrated to give the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm7.07-7.04 (m, 1H), 6.57 (d, J=8.4 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H),2.19 (d, J=0.7 Hz, 3H), 1.77-1.73 (m, 2H), 1.33-1.26 (m, 2H). MS (ESI)m/z=235 (M−H)⁻.

Example I-40E1-(2,6-dimethoxy-3-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

To a mixture of 1-(2,6-dimethoxy-3-methylphenyl)cyclopropanecarboxylicacid (40 mg, 0.17 mmol) from Example I-40D, EDAC(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl, 65 mg, 0.34 mmol)and 4-dimethylaminopyridine (23 mg, 0.19 mmol) in anhydrousdichloromethane (600 μL) was added naphthalene-1-sulfonamide (44 mg,0.21 mmol). The solution was stirred at ambient temperature three hours,concentrated and purified by reverse-phase HPLC [Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20 to 70% gradient ofacetonitrile in 0.1% aqueous trifluoroacetic acid] to give the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.43 (bs, 1H),8.64-8.58 (m, 1H), 8.28-8.22 (m, 2H), 8.12-8.07 (m, 1H), 7.72-7.63 (m,3H), 7.09-7.05 (m, 1H), 6.63 (d, J=8.4 Hz, 1H), 3.54 (s, 3H), 3.21 (s,3H), 2.06 (s, 3H), 1.52-1.46 (m, 2H), 1.04-0.99 (m, 2H). MS (ESI) m/z426 (M+H)+.

Example I-411-(2,6-dimethoxy-3-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of 1-(2,6-dimethoxy-3-methylphenyl)cyclopropanecarboxylic acid(24 mg, 0.10 mmol) from Example I-40D, quinoline-5-sulfonamide (25 mg,0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (38 mg, 0.20mmol) and 4-dimethylaminopyridine (14 mg, 0.11 mmol) in anhydrousN,N-dimethylacetamide (600 μL) was stirred at ambient temperature for 16hours. The mixture was purified by reverse-phase HPLC [Waters XBridge™C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 10 to 60%gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid] to givethe title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.56(bs, 1H), 9.08-9.03 (m, 2H), 8.36-8.31 (m, 2H), 7.94 (dd, J=8.4, 7.5 Hz,1H), 7.74 (dd, J=8.6, 4.4 Hz, 1H), 7.11-7.07 (m, 1H), 6.64 (d, J=8.4 Hz,1H), 3.54 (s, 3H), 3.30 (s, 3H), 2.08 (s, 3H), 1.50-1.45 (m, 2H),1.06-1.01 (m, 2H). MS (ESI) m/z 427 (M+H)⁺.

Example I-421-(2,6-dimethoxy-3-methylphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

A mixture of 1-(2,6-dimethoxy-3-methylphenyl)cyclopropanecarboxylic acid(24 mg, 0.10 mmol) from Example I-40D, 1H-indole-4-sulfonamide (24 mg,0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (38 mg, 0.20mmol) and 4-dimethylaminopyridine (14 mg, 0.11 mmol) in anhydrousN,N-dimethylacetamide (600 μL) was stirred at ambient temperature for 16hours and was purified by reverse-phase HPLC [Waters XBridge™ C18 5 μmOBD column, 30×100 mm, flow rate 40 mL/minute, 10 to 70% gradient ofacetonitrile in 0.1% aqueous trifluoroacetic acid] to give the titlecompound. ¹H NMR (501 MHz, CD₂Cl₂/CD₃OD) δ ppm 9.94 (bs, 1H), 7.79 (dd,J=7.5, 0.9 Hz, 1H), 7.71-7.68 (m, 1H), 7.40-7.38 (m, 1H), 7.27 (dd,J=8.1, 7.5 Hz, 1H), 7.19-7.16 (m, 1H), 6.71-6.69 (m, 1H), 6.67 (d, J=8.4Hz, 1H), 3.72 (s, 3H), 3.55 (s, 3H), 2.20-2.18 (m, 3H), 1.52-1.47 (m,2H), 1.13-1.05 (m, 2H). MS (ESI) m/z 415 (M+H)⁺.

Example I-431-(2,6-dimethoxy-3-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of 1-(2,6-dimethoxy-3-methylphenyl)cyclopropanecarboxylic acid(40 mg, 0.17 mmol) from Example I-40D, 2-methylquinoline-5-sulfonamide(47 mg, 0.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (65mg, 0.34 mmol) and 4-dimethylaminopyridine (23 mg, 0.19 mmol) inanhydrous N,N-dimethylacetamide (1.0 mL) was stirred at ambienttemperature for 16 hours and then purified by reverse-phase HPLC [WatersXBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 10 to60% gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid] togive the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm8.99 (d, J=8.9 Hz, 1H), 8.27-8.24 (m, 2H), 7.91 (dd, J=8.0 Hz, 1H), 7.68(d, J=8.9 Hz, 1H), 7.11-7.08 (m, 1H), 6.65 (d, J=8.4 Hz, 1H), 3.56 (s,3H), 3.31 (s, 3H), 2.75 (s, 3H), 2.09-2.08 (m, 3H), 1.50-1.45 (m, 2H),1.06-1.01 (m, 2H). MS (ESI) m/z 441 (M+H)⁺.

Example I-441-(2-methoxy-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-44A Methyl 1-(2-methoxy-5-methylphenyl)cyclopropanecarboxylate

To a solution of bis(dibenzylideneacetone)palladium (0.029 g, 0.050mmol) and Q-Phos (pentaphenyl(di-tert-butylphosphino)ferrocene, 0.035 g,0.050 mmol) in tetrahydrofuran (10 mL) at ambient temperature was added2-bromo-1-methoxy-4-methylbenzene (Aldrich, CAS #23002-45-5) (0.359 mL,2.487 mmol) followed by a solution of freshly prepared(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (12.43 mL, 4.97 mmol).The mixture was stirred at ambient temperature for 16 hours. Ethylacetate and saturated aqueous ammonium chloride were added. The organiclayer was washed with brine and concentrated. The residue was purifiedvia chromatography on a 24 g silica gel cartridge, eluting with ethylacetate in heptane at 0-30% gradient over a period of 15 minutes toprovide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm7.08-7.03 (m, 1H), 7.00 (d, J=2.2 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 3.80(s, 3H), 3.60 (s, 3H), 2.31 (s, 3H), 1.58 (q, J=4.0 Hz, 2H), 1.13-1.07(m, 2H). MS (APCI+) m/z 221 (M+H)⁺.

Example I-44B 1-(2-methoxy-5-methylphenyl)cyclopropanecarboxylic Acid

Methyl 1-(2-methoxy-5-methylphenyl)cyclopropanecarboxylate from ExampleI-44A (0.465 g, 2.111 mmol) was dissolved in tetrahydrofuran (5.00 mL),methanol (5.00 mL) and water (5 mL) and treated with sodium hydroxide(0.439 g, 10.98 mmol). After 4 hours at 60° C., the reaction mixture wasconcentrated, cooled in an ice bath and carefully quenched with 3 Naqueous HCl (about 3.5 mL) until the pH was acidic. The resulting slurrywas stirred vigorously and filtered. The precipitate was washed withwater and dried in a vacuum oven for 16 hours to provide the titlecompound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.91 (s, 1H),7.02 (ddd, J=8.2, 2.3, 0.9 Hz, 1H), 6.99-6.93 (m, 1H), 6.83 (d, J=8.2Hz, 1H), 3.73 (s, 3H), 2.21 (s, 3H), 1.38 (q, J=3.9 Hz, 2H), 0.99 (q,J=3.9 Hz, 2H). MS (APCI+) m/z 207 (M+H)⁺.

Example I-44C1-(2-methoxy-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of 1-(2-methoxy-5-methylphenyl)cyclopropanecarboxylic acidfrom Example I-44B (0.100 g, 0.485 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (0.186 g, 0.970 mmol) and N,N-dimethylpyridin-4-amine(0.065 g, 0.533 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (0.101 g, 0.485 mmol). After 5 hours, thereaction was quenched with 3.5 mL of aqueous 1 N HCl and the organiclayer was concentrated in vacuo. The residue was purified viachromatography on a 24 g silica gel cartridge, eluting with ethylacetate in heptane at a 0-50% gradient over a period of 10 minutes. Thecrude material was triturated with methanol and filtered to provide thetitle compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.55 (s,1H), 9.05 (dd, J=4.2, 1.6 Hz, 1H), 8.98 (dd, J=8.7, 1.1 Hz, 1H), 8.34(d, J=8.5 Hz, 1H), 8.30 (d, J=7.4 Hz, 1H), 7.93 (t, J=7.9 Hz, 1H), 7.70(dd, J=8.8, 4.2 Hz, 1H), 7.10-7.03 (m, 1H), 6.94 (d, J=2.2 Hz, 1H), 6.76(d, J=8.3 Hz, 1H), 3.33 (s, 3H), 2.23 (s, 3H), 1.22 (q, J=4.3 Hz, 2H),0.93 (q, J=4.4 Hz, 2H). MS (APCI+) m/z 397 (M+H)⁺.

Example I-451-(2-ethoxy-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-45A Methyl 1-(2-ethoxy-6-methoxyphenyl)cyclopropanecarboxylate

A solution of Example I-46A (methyl1-(2-hydroxy-6-methoxyphenyl)cyclopropanecarboxylate) (25 mg, 0.112mmol) and ethyl iodide (31.8 μl, 0.394 mmol) in N,N-dimethylformamide(0.5 mL) was treated with a 60% dispersion of sodium hydride in mineraloil (13.50 mg, 0.337 mmol), stirred at ambient temperature for 20minutes, and partitioned between methyl tert-butyl ether (30 mL) and 1 Maqueous HCl (10 mL). The methyl tert-butyl ether layer was washed withwater (5 mL), washed with brine, dried (MgSO₄), filtered, concentratedand chromatographed on silica gel, eluting with a gradient of 5% to 30%ethyl acetate in heptanes to provide the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 7.19 (t, J=8.3 Hz, 1H), 6.52 (d, J=8.4 Hz, 2H), 4.03(q, J=7.0 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 3H), 1.66 (q, J=4.3 Hz, 2H),1.37 (t, J=7.0 Hz, 3H), 1.14 (q, J=4.4 Hz, 2H).

Example I-45B 1-(2-ethoxy-6-methoxyphenyl)cyclopropanecarboxylic Acid

A solution of Example I-45A (methyl1-(2-ethoxy-6-methoxyphenyl)cyclopropanecarboxylate) (25 mg, 0.100 mmol)in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) was treated with 3 Maqueous NaOH (1 mL) and heated to 60° C. for 30 minutes, heated to 80°C. for 8 hours, cooled and partitioned between methyl tert-butyl ether(50 mL) and 1 M aqueous HCl (15 mL). The methyl tert-butyl ether layerwas washed with brine, dried (MgSO₄), filtered, and concentrated toprovide the title compound. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.18 (t, J=8.3Hz, 1H), 6.51 (d, J=8.4 Hz, 2H), 4.03 (q, J=7.0 Hz, 2H), 3.81 (s, 3H),1.71 (q, J=4.3 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H), 1.21-1.19 (m, 2H).

Example I-45C1-(2-ethoxy-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

A solution of Example I-45B(1-(2-ethoxy-6-methoxyphenyl)cyclopropanecarboxylic acid) (21 mg, 0.089mmol), quinoline-5-sulfonamide (27.8 mg, 0.133 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34.1 mg,0.178 mmol) in N,N-dimethylformamide (0.3 mL) was treated with4-dimethylaminopyridine (21.72 mg, 0.178 mmol) and stirred over night atambient temperature. The mixture was partitioned between methyltert-butyl ether (50 mL) and 1 M aqueous HCl (15 mL). The methyltert-butyl ether layer was washed with 0.2 M aqueous HCl (15 mL), washedwith brine, dried (MgSO₄), filtered, concentrated and chromatographed onsilica gel, eluting with a gradient of 25% to 100% [200:1:1 ethylacetate:formic acid:H₂O] in heptanes to provide the title compound. ¹HNMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.25 (bs, 1H), 9.05 (dd,J=1.6, 4.1 Hz, 1H), 9.00-8.97 (m, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.29 (dd,J=1.3, 7.5 Hz, 1H), 7.92 (dd, J=7.5, 8.4 Hz, 1H), 7.70 (dd, J=4.1, 8.8Hz, 1H), 7.21 (t, J=8.3 Hz, 1H), 6.57 (d, J=8.1 Hz, 1H), 6.53 (d, J=8.2Hz, 1H), 3.79 (q, J=7.0 Hz, 2H), 3.62 (s, 3H), 1.39 (q, J=4.3 Hz, 2H),0.92 (q, J=4.4 Hz, 2H), 0.87 (t, J=6.9 Hz, 3H). LC/MS (APCI+) m/z 427(M+H)⁺.

Example I-461-[2-(cyclopropylmethoxy)-6-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-46A Methyl1-(2-hydroxy-6-methoxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-7A (methyl1-(2,6-dimethoxyphenyl)cyclopropanecarboxylate) (0.5 g, 2.116 mmol) indichloromethane (20 mL, anhydrous) under nitrogen at −78° C. was treatedwith 1 M BBr₃ in dichloromethane (2.96 mL, 2.96 mmol) over approximatelythree minutes. The mixture was stirred at −78° C. for two hours. Themixture was poured into rapidly stirred 1 M aqueous HCl (20 mL) at 0° C.over 30 seconds. The mixture was transferred to a separatory funnel,shaken, and the layers were separated. The aqueous layer was extractedwith additional dichloromethane (˜25 mL). The combined dichloromethanelayers were dried (MgSO₄), filtered, concentrated, and chromatographedon silica gel, eluting with a gradient of 15% to 50% ethyl acetate inheptanes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm7.15 (t, J=8.2 Hz, 1H), 6.53 (dd, J=1.0, 8.2 Hz, 1H), 6.47 (dd, J=1.0,8.3 Hz, 1H), 5.45 (s, 1H), 3.81 (s, 3H), 3.63 (s, 3H), 1.75 (q, J=4.0Hz, 2H), 1.17 (q, J=3.8 Hz, 2H).

Example I-46B Methyl1-(2-(cyclopropylmethoxy)-6-methoxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-46A (methyl1-(2-hydroxy-6-methoxyphenyl)cyclopropanecarboxylate) (25 mg, 0.112mmol) and (iodomethyl)cyclopropane (102 mg, 0.562 mmol) inN,N-dimethylformamide (0.5 mL) was treated with a 60% dispersion ofsodium hydride in mineral oil (13.50 mg, 0.337 mmol), stirred at ambienttemperature for 15 minutes, and partitioned between methyl tert-butylether (30 mL) and 1 M aqueous HCl (10 mL). The methyl tert-butyl etherlayer was washed with water (5 mL), washed with brine, dried (MgSO₄),filtered, concentrated, and chromatographed on silica gel, eluting witha gradient of 5% to 30% ethyl acetate in heptanes to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.18 (t, J=8.3 Hz, 1H),6.54-6.48 (m, 2H), 3.84 (d, J=6.4 Hz, 2H), 3.81 (s, 3H), 3.59 (s, 3H),1.69-1.66 (m, 2H), 1.27-1.19 (m, 1H), 1.18-1.15 (m, 2H), 0.59-0.54 (m,2H), 0.35-0.30 (m, 2H). LC/MS (APCI+) m/z 277 (M+H)⁺.

Example I-46C1-(2-(cyclopropylmethoxy)-6-methoxyphenyl)cyclopropane-1-carboxylic Acid

A solution of Example I-46B (methyl1-(2-(cyclopropylmethoxy)-6-methoxyphenyl)cyclopropanecarboxylate) (25mg, 0.090 mmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) wastreated with 3 M aqueous NaOH (1 mL), heated to 60° C. for 30 minutes,heated to 80° C. for 8 hours, cooled and partitioned between methyltert-butyl ether (50 mL) and 1 M aqueous HCl (15 mL). The methyltert-butyl ether layer was washed with brine, dried (MgSO₄), filtered,and concentrated to provide the title compound. ¹H NMR (400 MHz, CDCl₃)δ ppm 7.18 (t, J=8.3 Hz, 1H), 6.53-6.48 (m, 2H), 3.84 (d, J=6.6 Hz, 2H),3.81 (s, 3H), 1.73 (q, J=4.3 Hz, 2H), 1.29-1.19 (m, 3H), 0.61-0.55 (m,2H), 0.36-0.31 (m, 2H). LC/MS (APCI+) m/z 263 (M+H)⁺.

Example I-46D1-[2-(cyclopropylmethoxy)-6-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

A solution of Example I-46C(1-(2-(cyclopropylmethoxy)-6-methoxyphenyl)cyclopropanecarboxylic acid)(21.4 mg, 0.082 mmol), quinoline-5-sulfonamide (25.5 mg, 0.122 mmol) and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.3 mg,0.163 mmol) in N,N-dimethylformamide (0.3 mL) was treated with4-dimethylaminopyridine (19.93 mg, 0.163 mmol) and stirred for 16 hoursat ambient temperature. The mixture was partitioned between methyltert-butyl ether (50 mL) and 1 M aqueous HCl (15 mL). The methyltert-butyl ether layer was washed with 0.2 M aqueous HCl (15 mL), washedwith brine, dried (MgSO₄), filtered, concentrated, and chromatographedon silica gel, eluting with a gradient of 25% to 100% [200:1:1 ethylacetate:HCOOH:H₂O] in heptanes to provide the title compound. ¹H NMR(400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.23 (bs, 1H), 9.04 (dd, J=1.6,4.2 Hz, 1H), 8.99 (dt, J=1.3, 8.7 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.29(dd, J=1.2, 7.4 Hz, 1H), 7.92 (dd, J=7.4, 8.5 Hz, 1H), 7.70 (dd, J=4.1,8.8 Hz, 1H), 7.20 (t, J=8.3 Hz, 1H), 6.57 (d, J=8.2 Hz, 1H), 6.53 (d,J=8.1 Hz, 1H), 3.66 (d, J=6.3 Hz, 2H), 3.61 (s, 3H), 1.41 (q, J=4.4 Hz,2H), 0.95 (q, J=4.5 Hz, 2H), 0.81-0.72 (m, 1H), 0.26-0.21 (m, 2H),0.07-0.03 (m, 2H). LC/MS (APCI+) m/z 453 (M+H)⁺.

Example I-471-(6-methoxy-2,3-dimethylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-47A Methyl 1-(2-methoxy-6-methylphenyl)cyclopropanecarboxylate

To a solution of 2-bromo-1-methoxy-3-methylbenzene (Combi-Blocks CAS#38197-43-2) (1.024 g, 5.09 mmol) in tetrahydrofuran (25.5 mL) was addedbis(dibenzylideneacetone)palladium (0.059 g, 0.102 mmol) and Q-Phos(1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene)(pentaphenyl(di-tert-butylphosphino)ferrocene, 0.072 g, 0.102 mmol).Nitrogen was bubbled through the solution for about 3 minutes, then a0.4 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (25.5 mL, 10.19 mmol)was added dropwise over 5 minutes and the internal temperature rose from23.5° C. to 24.8° C. The reaction was stirred for 15 hours at ambienttemperature, at which point it was quenched with saturated aqueousammonium chloride (30 mL), diluted with methyl tert-butyl ether (130mL), and the layers were separated. The organic layer was filteredthrough a pad of silica gel. The filtrate was concentrated in vacuo togive a crude residue that was purified via flash chromatography, elutingon a 40 g silica gel cartridge with 1-40% ethyl acetate/heptanes over 40minutes to provide the title compound. ¹H NMR (400 MHz, CDCl₃) δ ppm7.15 (t, J=7.9 Hz, 1H), 6.76-6.80 (m, 1H), 6.73 (d, J=8.2 Hz, 1H), 3.80(s, 3H), 3.60 (s, 3H), 2.32 (s, 3H), 1.71-1.75 (m, 2H), 1.54 (s, 2H). MS(ESI+) m/z 221 (M+H)⁺, 243 (M+Na)⁺.

Example I-47B Methyl1-(3-bromo-6-methoxy-2-methylphenyl)cyclopropanecarboxylate

A solution of methyl 1-(2-methoxy-6-methylphenyl)cyclopropanecarboxylatefrom Example I-47A (0.551 g, 2.502 mmol) and benzyltrimethylammoniumtribromide (1.0656 g, 2.73 mmol) in tetrahydrofuran (7.82 mL) anddegassed water (4.69 mL) was stirred at ambient temperature for 16hours. The volatiles were removed in vacuo and the resulting crudematerial was diluted with 100 mL of methyl tert-butyl ether. Theorganics were filtered through a pad of silica gel. The filtrate wasconcentrated to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.45 (d, J=8.8 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 3.80(s, 3H), 3.62 (s, 3H), 2.41 (s, 3H), 1.78 (tt, J=6.8, 3.4 Hz, 2H),1.28-1.16 (m, 1H), 1.07-0.95 (m, 1H).

Example I-47C Methyl1-(6-methoxy-2,3-dimethylphenyl)cyclopropanecarboxylate

A solution of methyl1-(3-bromo-6-methoxy-2-methylphenyl)cyclopropanecarboxylate from ExampleI-47B (233 mg, 0.779 mmol), potassium carbonate (431 mg, 3.12 mmol),trimethylboroxine (436 μl, 3.12 mmol) in 1,4-dioxane (6676 μl) and water(1113 μl) was degassed with bubbling nitrogen for 10 minutes.1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (254 mg, 0.312 mmol) was added. The reaction washeated at 90° C. with stirring for 16 hours. The solvent was reduced involume and the crude material was diluted with ethyl acetate andfiltered through a 4 μM syringe filter. The solvent was removed and thecrude material was chromatographed using a 24 g silica gel cartridgewith 0-100% ethyl acetate/heptanes over a period of 20 minutes toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.06(d, J=8.3 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 3.80 (s, 3H), 3.62 (s, 3H),2.25 (s, 3H), 2.22 (s, 3H), 1.77 (t, J=3.3 Hz, 2H), 1.23 (d, J=10.2 Hz,1H), 1.02 (d, J=6.0 Hz, 1H).

Example I-47D 1-(6-methoxy-2,3-dimethylphenyl)cyclopropanecarboxylicAcid

Methyl 1-(6-methoxy-2,3-dimethylphenyl)cyclopropanecarboxylate fromExample I-47C (0.165 g, 0.704 mmol) was dissolved in tetrahydrofuran(0.5 mL) and methanol (0.500 mL), and water (0.5 mL). The mixture wastreated with sodium hydroxide (0.197 g, 4.93 mmol) and stirred atambient temperature for 16 hours, and at 70° C. for 5 hours. Thereaction mixture was concentrated, cooled in an ice bath and carefullyquenched with 12 N aqueous HCl (about 1.0 mL) until the pH was acidic.The resulting slurry was stirred vigorously and filtered, and theprecipitate was washed with water and dried in a vacuum oven for 16hours to provide the title compound. ¹H NMR (400 MHz, chloroform-d) δppm 11.22 (s, 1H), 7.06 (d, J=8.3 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 3.80(s, 3H), 2.27 (s, 3H), 2.21 (s, 3H), 1.88-1.75 (m, 2H), 1.35-1.23 (m,1H), 1.13-1.00 (m, 1H).

Example I-47E1-(6-methoxy-2,3-dimethylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of 1-(6-methoxy-2,3-dimethylphenyl)cyclopropanecarboxylicacid from Example I-47D (52 mg, 0.236 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (91 mg, 0.472 mmol) and N,N-dimethylpyridin-4-amine (28.8mg, 0.236 mmol) in anhydrous dimethylacetamide (1 mL) was addedquinoline-5-sulfonamide (54.1 mg, 0.260 mmol). After 16 hours thereaction was diluted with 1 mL of saturated aqueous ammonium chloridethen quenched with 0.5 mL of 1 N aqueous HCl to give a cloudy mixture.The mixture was extracted with 3×2 mL of dichloromethane using anaqueous/organic extractor tube. The solvent was removed and the crudematerial was taken up in dimethylsulfoxide and methanol (1:1) andpurified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2)5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A)and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound. ¹H NMR (400 MHz, chloroform-d)δ ppm 9.50 (d, J=8.7 Hz, 1H), 9.34 (d, J=4.9 Hz, 1H), 8.76 (d, J=8.6 Hz,1H), 8.65 (dd, J=7.5, 1.0 Hz, 1H), 8.41 (s, 1H), 8.17-8.08 (m, 1H), 7.92(dd, J=8.9, 4.6 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H),3.76 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H), 1.73 (ddd, J=10.0, 7.7, 4.0Hz, 1H), 1.52 (ddd, J=9.9, 7.5, 4.5 Hz, 1H), 1.11 (ddd, J=9.4, 7.7, 4.4Hz, 1H), 0.96 (ddd, J=9.4, 7.5, 4.0 Hz, 1H). MS (APCI+) m/z 411 (M+H)⁺.

Example I-481-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-48A Methyl1-(3-cyclopropyl-6-methoxy-2-methylphenyl)cyclopropanecarboxylate

A mixture of methyl1-(3-bromo-6-methoxy-2-methylphenyl)cyclopropanecarboxylate from ExampleI-47B (286 mg, 0.956 mmol), potassium cyclopropyltrifluoroborate (170mg, 1.147 mmol), palladium(II) acetate (21.46 mg, 0.096 mmol), butyldi-1-adamantylphosphine (51.4 mg, 0.143 mmol), and cesium carbonate (934mg, 2.87 mmol) was flushed with nitrogen, combined with toluene (5295μl, 49.7 mmol) and degassed with a stream of nitrogen for 15 minutes.The mixture was treated with degassed water (637 μl, 35.4 mmol) andstirred at 90° C. for 18 hours. The solvent was reduced in volume andthe crude organics were applied directly to a 24 g silica gel cartridgeand purified using a gradient of 5-100% ethyl acetate/hexanes to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.00 (d, J=8.4Hz, 1H), 6.67 (d, J=8.5 Hz, 1H), 3.79 (s, 3H), 3.62 (s, 3H), 2.43 (s,3H), 1.86-1.72 (m, 3H), 1.28-1.20 (m, 1H), 1.08-0.99 (m, 1H), 0.94-0.83(m, 2H), 0.64-0.49 (m, 2H).

Example I-48B1-(3-cyclopropyl-6-methoxy-2-methylphenyl)cyclopropanecarboxylic Acid

Methyl 1-(3-cyclopropyl-6-methoxy-2-methylphenyl)cyclopropanecarboxylatefrom Example I-48A (0.171 g, 0.657 mmol) was dissolved intetrahydrofuran (0.5 mL), methanol (0.500 mL), and water (0.5 mL). Themixture was treated with sodium hydroxide (0.229 g, 5.73 mmol) andstirred at ambient temperature for 16 hours, then at 70° C. for 5 hours.The reaction was concentrated, cooled in an ice bath and carefullyquenched with 12 N aqueous HCl (about 1.0 mL) until the pH was acidic.The resulting slurry was stirred vigorously and filtered. The materialwas washed with water and dried in a vacuum oven for 16 hours to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 6.99 (d, J=8.5Hz, 1H), 6.65 (d, J=8.5 Hz, 1H), 3.80 (s, 3H), 2.45 (s, 3H), 1.86-1.75(m, 3H), 1.32-1.21 (m, 1H), 1.09 (dd, J=9.5, 4.4 Hz, 1H), 0.92-0.82 (m,2H), 0.60-0.52 (m, 2H).

Example I-48C1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(3-cyclopropyl-6-methoxy-2-methylphenyl)cyclopropanecarboxylic acidfrom Example I-48B (57 mg, 0.231 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (89 mg, 0.463 mmol) and N,N-dimethylpyridin-4-amine (28.3mg, 0.231 mmol) in anhydrous N,N-dimethylacetamide (1 mL) was addedquinoline-5-sulfonamide (53.0 mg, 0.255 mmol). After 16 hours, thereaction was diluted with 1 mL of water and quenched with 0.5 mL of 1 Naqueous HCl. A precipitate formed. The precipitate was washed withwater, dried under a stream of nitrogen, added to 1 mL of methanol,heated to dissolve, cooled, filtered, diluted with 1 mL ofdimethylsulfoxide and purified by reverse-phase preparative HPLC on aPhenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). Agradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B)was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR(400 MHz, chloroform-d) δ ppm 9.23 (d, J=5.0 Hz, 1H), 9.20 (d, J=9.0 Hz,1H), 8.65 (d, J=8.6 Hz, 1H), 8.61 (dd, J=7.5, 1.0 Hz, 1H), 8.36 (s, 1H),8.03 (dd, J=8.5, 7.4 Hz, 1H), 7.77 (dd, J=8.8, 4.5 Hz, 1H), 7.11 (d,J=8.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 3.75 (d, J=0.9 Hz, 3H), 2.24 (s,3H), 1.75 (tdd, J=11.6, 8.1, 4.7 Hz, 2H), 1.52 (ddd, J=10.0, 7.4, 4.4Hz, 1H), 1.10 (ddd, J=9.7, 7.7, 4.4 Hz, 1H), 1.04-0.88 (m, 3H), 0.61(ddt, J=13.1, 9.3, 4.8 Hz, 2H). MS (APCI+) m/z 437 (M+H)⁺.

Example I-49N-(1H-indole-4-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamideExample I-49A Methyl 1-(2-methoxy-5-methylphenyl)cyclopropanecarboxylate

To a solution of bis(dibenzylideneacetone)palladium (0.029 g, 0.050mmol) and 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene(0.035 g, 0.050 mmol) in tetrahydrofuran (10 mL) at ambient temperaturewas added 2-bromo-1-methoxy-4-methylbenzene (0.359 mL, 2.487 mmol)followed by a solution of freshly-prepared(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (12.43 mL, 4.97 mmol).The mixture was stirred at ambient temperature for 16 hours. Ethylacetate and saturated aqueous NH₄Cl were added. The organic layer waswashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified via chromatography on a 24 g silica gel cartridge,eluting with ethyl acetate in heptane at 0-30% gradient to provide thetitle compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.08-7.03 (m, 1H),7.00 (d, J=2.2 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 3.80 (s, 3H), 3.60 (s,3H), 2.27 (d, J=0.8 Hz, 3H), 1.58 (q, J=4.0 Hz, 2H), 1.13-1.07 (m, 2H).MS (APCI+) m/z 221 (M+H)+.

Example I-49B 1-(2-methoxy-5-methylphenyl)cyclopropanecarboxylic Acid

Example I-49A (0.465 g, 2.111 mmol) in a mixture of tetrahydrofuran (5mL), methanol (5 mL) and water (5 mL) was treated with sodium hydroxide(0.439 g, 10.98 mmol). The mixture was stirred at 60° C. for 4 hours.The solvent was removed and the pH was adjusted to 1-2 by adding 2 Naqueous HCl. The resulting slurry was vigorously stirred and theprecipitated was filtered, washed with water and dried in a vacuum ovenfor 16 hours to provide the title compound. ¹H NMR (501 MHz, dimethylsulfoxide-d₆) 6 ppm 11.91 (s, 1H), 7.02 (ddd, J=8.2, 2.3, 0.9 Hz, 1H),6.99-6.93 (m, 1H), 6.83 (d, J=8.2 Hz, 1H), 3.73 (s, 3H), 2.21 (s, 3H),1.38 (q, J=3.9 Hz, 2H), 0.99 (q, J=3.9 Hz, 2H). MS (APCI+) m/z 189(M+H-H2O)⁺.

Example I-49C Tert-Butyl 4-bromo-1H-indole-1-carboxylate

Di-tert-butyl dicarbonate (5.33 mL, 22.95 mmol) was added to a solutionof 4-bromo-1H-indole (3.00 g, 15.30 mmol) and DMAP(4-dimethylaminopyridine) (0.187 g, 1.530 mmol)) in tetrahydrofuran (20mL). The reaction mixture was stirred for 30 minutes. The mixture waspartitioned between ether (100 mL) and water (100 mL). The ether layerwas washed with (3×50 mL) of saturated aqueous sodium bicarbonate and 75mL of brine. The ether layer was dried over magnesium sulfate, filteredand concentrated. The residue was chromatographed over silica geleluting with 1:100 ethyl acetate:petroleum ether to afford the titlecompound.

Example I-49D N-cyclohexyl-N-methylcyclohexanaminium1-(tert-butoxycarbonyl)-1H-indole-4-sulfinate

An 20 mL microwave vial was charged with tert-butyl4-bromo-1H-indole-1-carboxylate (500 mg, 1.688 mmol),1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate (406 mg, 1.688mmol) and PdCl₂(AmPhos)₂(bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),71.7 mg, 0.101 mmol). A solution of N-cyclohexyl-N-methylcyclohexanamine(1.091 mL, 5.06 mmol) in anhydrous isopropyl alcohol (10 mL) was added,the vial was sealed with a Teflon cap, sparged for 5 minutes withnitrogen and subjected to microwave conditions at 110° C. for 1 hour.After cooling to ambient temperature, the mixture was filtered to givethe crude title compound solution which was used without furtherpurification. MS (ESI+) m/z 282.2 (M+H)⁺.

Example I-49E Tert-Butyl 4-sulfamoyl-1H-indole-1-carboxylate

To a solution of crude 1-(tert-butoxycarbonyl)-1H-indole-4-sulfinate(940 mg, 3.35 mmol) in isopropyl alcohol (20 mL), water (40 mL) wasadded, followed by sodium acetate trihydrate (1369 mg, 10.06 mmol) and(aminooxy)sulfonic acid (1138 mg, 10.06 mmol). The mixture was stirredat ambient temperature for 2 hours. The mixture was concentrated underreduced pressure to provide the solution of crude product. The crudematerial was purified by silica gel chromatography (40% of ethyl acetatein petroleum) to give title compound. MS (ESI+) m/z 319 (M+23)⁺.

Example I-49F 1H-indole-4-sulfonamide

To a solution of tert-butyl 4-sulfamoyl-1H-indole-1-carboxylate (800 mg,2.70 mmol) in dichloromethane (16 mL) cooled to 0° C.,2,2,2-trifluoroacetic acid (8 mL, 2.70 mmol) was added. The reactionmixture was stirred at 0° C. for 3 hours. After completion, the mixturewas concentrated under reduced pressure to give crude title compound.The crude material was washed with water (10 mL×2), methanol (5 mL×2),and dichloromethane (5 mL×2) to provide the title compound. ¹H NMR (400MHz, dimethyl sulfoxide-d₆) δ ppm 11.54 (s, 1H), 7.63 (d, J=8.1 Hz, 1H),7.57-7.52 (m, 1H), 7.50 (d, J=7.4 Hz, 1H), 7.25 (s, 2H), 7.20 (t, J=7.8Hz, 1H), 6.86 (s, 1H). MS (ESI+) m/z 197.1 (M+H)⁺.

Example I-49GN-(1H-indol-4-ylsulfonyl)-1-(2-methoxy-5-methyl-phenyl)cyclopropanecarboxamide

Example I-49B (26 mg, 0.125 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine,hydrochloric acid (48.8 mg, 0.255 mmol) and N,N-dimethylpyridin-4-amine(31.1 mg, 0.255 mmol) in dichloromethane (4 mL) was stirred at ambienttemperature for 30 minutes. 1H-Indole-4-sulfonamide (25 mg, 0.127 mmol)was added. The mixture was stirred at 45° C. for 2 hours. The solventwas removed and the residue was purified via HPLC with reverse phaseHPLC (C18, CH₃CN/H₂O (0.1% trifluoroacetic acid)=5-95%, 20 minutes) toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.63 (s, 1H), 10.86 (s, 1H), 7.71 (dt, J=8.1, 1.0 Hz, 1H),7.61-7.53 (m, 2H), 7.23 (t, J=7.8 Hz, 1H), 7.10-7.03 (m, 1H), 6.94 (d,J=2.3 Hz, 1H), 6.85-6.77 (m, 2H), 3.49 (s, 3H), 2.22 (s, 3H), 1.24 (q,J=4.2 Hz, 2H), 0.93 (q, J=4.4 Hz, 2H). MS (APCI+) m/z 385.24 (M+H)⁺.

Example I-501-[2-methoxy-6-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-50A 2-isopropyl-6-methoxyaniline

To a solution of 2-bromo-6-methoxyaniline (AK-90829) (1.000 mL, 7.55mmol) in tetrahydrofuran (10 mL) was added Pd-PEPPSI-IPent-Cl(dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II),0.208 g, 0.242 mmol). Nitrogen was bubbled through the solution forabout 3 minutes, then a 0.4 M in tetrahydrofuran solution ofisopropylzinc(II) bromide (52 mL, 20.80 mmol) was added dropwise over 5minutes, with nitrogen flushing through the system and the internaltemperature rising slowly from 21° C. to 32° C. The reaction mixture wasstirred for 15 hours at ambient temperature, at which point it wasquenched with saturated aqueous ammonium chloride (50 mL), diluted withmethyl tert-butyl ether (400 mL), and the layers were separated. Theorganic layer was filtered through a pad of silica gel and concentratedin vacuo. The crude material was purified via flash chromatography,eluting on a 40 g silica gel cartridge with 1-40% ethyl acetate/heptanesover 40 minutes to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 6.89-6.66 (m, 3H), 3.87 (s, 3H), 3.86 (s, 2H), 2.96(hept, J=6.8 Hz, 1H), 1.28 (d, J=6.9 Hz, 6H).

Example I-50B Methyl1-(2-isopropyl-6-methoxyphenyl)cyclopropanecarboxylate

To a cooled (−5° C.) suspension of 2-isopropyl-6-methoxyaniline fromExample I-50A (0.942 g, 5.70 mmol) in 20% aqueous sulfuric acid (10 mL)was added a solution of sodium nitrite (0.393 g, 5.70 mmol) in water (2mL) dropwise. The starting material slowly dissolved upon the dropwiseaddition of the sodium nitrite, and the resulting mixture was stirred inthe ice bath for 1 hour, then was added slowly to a cooled solution ofcopper(I) bromide (1.227 g, 8.55 mmol) in 40% aqueous HBr (6.75 mL). Themixture was warmed to 60° C. for 16 hours, then cooled to ambienttemperature and extracted with 3×50 mL of ethyl acetate. The combinedextracts were washed with saturated aqueous sodium bicarbonate andbrine, dried over sodium sulfate, filtered, and concentrated in vacuo.The crude product was chromatographed using a 10 g silica gel cartridgewith a methyl tert-butyl ether/hexanes solvent system to give2-bromo-1-isopropyl-3-methoxybenzene. To a solution of crude2-bromo-1-isopropyl-3-methoxybenzene (0.227 g, 0.991 mmol) intetrahydrofuran (4.95 mL) was added bis(dibenzylideneacetone)palladium(0.011 g, 0.020 mmol) and Q-Phos(1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene)(pentaphenyl(di-tert-butylphosphino)ferrocene, 0.014 g, 0.020 mmol).Nitrogen was bubbled through the solution for about 3 minutes, then a0.4 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (4.95 mL, 1.982 mmol)was added dropwise over 5 minutes and the internal temperature rose from17.2° C. to 21.0° C. The reaction was stirred for 15 hours at ambienttemperature, at which point it was quenched with saturated ammoniumchloride (5 mL), diluted with methyl tert-butyl ether (30 mL), and thelayers were separated. The organic layer was filtered through a pad ofsilica gel and concentrated in vacuo. The crude material was purifiedvia flash chromatography, eluting on a 10 g silica gel cartridge with1-40% methyl tert-butyl ether/hexanes over 40 minutes to provide thetitle compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.32-7.26 (m, 1H),6.93 (dd, J=7.9, 1.1 Hz, 1H), 6.73 (dd, J=8.2, 1.1 Hz, 1H), 3.83 (s,3H), 3.63 (s, 3H), 3.46 (p, J=6.9 Hz, 1H), 1.81-1.75 (m, 2H), 1.29-1.22(m, 5H), 1.18 (d, J=6.8 Hz, 3H). MS (ESI+) m/z 221 (M+H)⁺.

Example I-50C 1-(2-isopropyl-6-methoxyphenyl)cyclopropanecarboxylic Acid

Methyl 1-(2-isopropyl-6-methoxyphenyl)cyclopropanecarboxylate fromExample I-50B (0.095 g, 0.383 mmol) was dissolved in tetrahydrofuran(0.5 mL) and methanol (0.500 mL), and water (0.5 mL), then treated withsodium hydroxide (0.113 g, 2.83 mmol) and warmed to 70° C. After 5 hoursat 70° C., the reaction was concentrated, cooled in an ice bath andcarefully quenched with 12 N aqueous HCl (about 0.2 mL) until the pH wasacidic. The resulting slurry was stirred vigorously and filtered. Thematerial was washed with water and dried in a vacuum oven for 16 hoursto provide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm7.32-7.25 (m, 1H), 6.93 (dd, J=7.9, 1.1 Hz, 1H), 6.73 (dd, J=8.1, 1.1Hz, 1H), 3.84 (s, 3H), 3.49 (h, J=6.7 Hz, 1H), 1.89-1.80 (m, 2H),1.32-1.23 (m, 4H), 1.20 (d, J=6.8 Hz, 3H), 1.15 (dd, J=9.4, 4.5 Hz, 1H).

Example I-50D1-[2-methoxy-6-(propan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of 1-(2-isopropyl-6-methoxyphenyl)cyclopropanecarboxylicacid from Example I-50C (70 mg, 0.299 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (115 mg, 0.598 mmol) and N,N-dimethylpyridin-4-amine (36.5mg, 0.299 mmol) in anhydrous N,N-dimethylacetamide (1.0 mL) was addedquinoline-5-sulfonamide (68.4 mg, 0.329 mmol). After 16 hours, thereaction was diluted with a small piece of ice and quenched with 0.5 mLof 1 N aqueous HCl and a precipitate formed. The precipitate was washedwith water, and dried under a stream of nitrogen. The crude material wastaken up in a small amount of 10% methanol/dichloromethane and purifiedusing a 10 g silica gel cartridge with a gradient of 0-10%methanol/dichloromethane to provide the title compound. ¹H NMR (501 MHz,chloroform-d) δ ppm 9.01 (dd, J=4.2, 1.6 Hz, 1H), 8.76 (ddd, J=8.8, 1.6,0.9 Hz, 1H), 8.52 (dd, J=7.4, 1.2 Hz, 1H), 8.41 (dt, J=8.5, 1.1 Hz, 1H),8.38 (s, 1H), 7.86 (dd, J=8.5, 7.4 Hz, 1H), 7.46 (dd, J=8.7, 4.1 Hz,1H), 7.39 (t, J=8.0 Hz, 1H), 6.96 (dd, J=8.0, 1.0 Hz, 1H), 6.81 (dd,J=8.2, 1.0 Hz, 1H), 3.79 (s, 3H), 3.32 (hept, J=6.9 Hz, 1H), 1.79 (ddd,J=10.2, 7.4, 3.7 Hz, 1H), 1.51 (ddd, J=9.6, 7.1, 4.2 Hz, 1H), 1.18 (d,J=6.8 Hz, 3H), 1.06 (ddd, J=9.4, 7.4, 4.2 Hz, 1H), 1.01 (dd, J=7.3, 3.9Hz, 1H), 0.98 (d, J=6.8 Hz, 3H). MS (APCI+) m/z 425 (M+H)⁺.

Example I-511-(2-cyclobutyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-51A 2-cyclobutyl-6-methoxyaniline

To a solution of 2-bromo-6-methoxyaniline (1.539 g, 7.62 mmol) intetrahydrofuran (12 mL) was added1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.297 g, 0.364 mmol). Nitrogen was bubbledthrough the solution for about 3 minutes, then a 0.35 M intetrahydrofuran solution of cyclobutylzinc(II) bromide (40 mL, 14.00mmol) was added dropwise over 5 minutes. The reaction was stirred for 15hours at ambient temperature. Additional cyclobutylzincbromide solution(24 mL) was added and the mixture was stirred at ambient temperature for24 hours. The reaction was quenched with saturated aqueous ammoniumchloride (50 mL), diluted with methyl tert-butyl ether (400 mL), and thelayers were separated. The organic layer was concentrated in vacuo togive crude material that was purified via flash chromatography, elutingon a 40 g silica gel cartridge with 1-60% methyl tert-butylether/hexanes over 40 minutes to provide the title compound. ¹H NMR (501MHz, chloroform-d) δ ppm 6.81 (ddd, J=7.5, 1.7, 0.8 Hz, 1H), 6.77 (t,J=7.7 Hz, 1H), 6.74 (dd, J=7.9, 1.8 Hz, 1H), 3.88 (s, 3H), 3.75 (d,J=17.6 Hz, 2H), 3.59-3.49 (m, 1H), 2.47-2.37 (m, 2H), 2.27-2.16 (m, 2H),2.09 (tdt, J=10.5, 9.3, 7.9 Hz, 1H), 1.95-1.86 (m, 1H). MS (ESI+) m/z178 (M+H)⁺.

Example I-51B Methyl1-(2-cyclobutyl-6-methoxyphenyl)cyclopropanecarboxylate

To a cooled (0° C.) suspension of 2-cyclobutyl-6-methoxyaniline fromExample I-51A (0.450 g, 2.54 mmol) in 40% aqueous HBr (1 mL) was added asolution of sodium nitrite (0.175 g, 2.54 mmol) in water (0.5 mL)dropwise, keeping the internal temperature below 5° C. The resultingmixture was stirred in the ice bath for 1 hour, then was added to asolution of copper(I) bromide (0.364 g, 2.54 mmol) in 40% aqueous HBr (1mL). The mixture was warmed to 85° C. for 1 hour, then cooled to ambienttemperature and extracted with 3×50 mL of methyl tert-butyl ether. Thecombined extracts were washed with saturated aqueous sodium bicarbonateand brine, and filtered through a pad of silica gel to give crude2-bromo-1-cyclobutyl-3-methoxybenzene. To a solution of the crude2-bromo-1-cyclobutyl-3-methoxybenzene (0.090 g, 0.373 mmol) intetrahydrofuran (1.866 mL) was added bis(dibenzylideneacetone)palladium(4.29 mg, 7.47 μmol) and Q-Phos(1,2,3,4,5-pentaphenylentaphenyl-1′-(di-tert-butylphosphino)ferrocene)(pentaphenyl(di-tert-butylphosphino)ferrocene, 5.31 mg, 7.47 μmol).Nitrogen was bubbled through the solution for about 3 minutes,pentaphenyla 0.4 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (1.866 mL, 0.747 mmol)was added dropwise over 5 minutes and the internal temperature rose from17.2° C. to 21.0° C. The reaction was stirred for 15 hours at ambienttemperature, at which point it was quenched with saturated aqueousammonium chloride (30 mL), diluted with methyl tert-butyl ether (130mL), and the layers were separated. The organic layer was filteredthrough a pad of silica gel and concentrated in vacuo to give crudematerial that was purified via flash chromatography, eluting on a 12 gsilica gel cartridge with 1-40% methyl tert-butyl ether/hexanes over 40minutes to provide the title compound. ¹H NMR (501 MHz, chloroform-d) δppm 7.32-7.27 (m, 1H), 7.02 (dt, J=7.7, 0.9 Hz, 1H), 6.77 (dd, J=8.1,1.1 Hz, 1H), 3.95-3.85 (m, 1H), 3.83 (s, 3H), 3.61 (s, 3H), 2.39-2.30(m, 1H), 2.29-2.19 (m, 2H), 2.13-1.97 (m, 2H), 1.90-1.81 (m, 1H),1.81-1.69 (m, 2H), 1.19-1.07 (m, 2H). MS (ESI+) m/z 221 (M+H)⁺.

Example I-51C 1-(2-cyclobutyl-6-methoxyphenyl)cyclopropanecarboxylicAcid

Methyl 1-(2-cyclobutyl-6-methoxyphenyl)cyclopropanecarboxylate fromExample I-51B (0.028 g, 0.108 mmol) was dissolved in tetrahydrofuran(0.5 mL) and methanol (0.500 mL), and water (0.5 mL), treated withsodium hydroxide (0.075 g, 1.875 mmol) and warmed to 70° C. After 3hours, the reaction was concentrated, cooled in an ice bath andcarefully quenched with 12 N aqueous HCl (about 0.2 mL) until the pH wasacidic. The crude material was taken up in methyl tert-butyl ether anddried over magnesium sulfate, filtered, and concentrated to provide thetitle compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.33-7.25 (m, 1H),7.02 (dd, J=7.8, 1.1 Hz, 1H), 6.76 (dd, J=8.2, 1.0 Hz, 1H), 3.95-3.85(m, 1H), 3.84 (s, 3H), 2.39-2.27 (m, 1H), 2.27-2.10 (m, 2H), 2.09-1.94(m, 1H), 1.92-1.76 (m, 3H), 1.24-1.15 (m, 3H). MS (DCI+) m/z 247 (M+H)⁺.

Example I-51D1-(2-cyclobutyl-6-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of 1-(2-cyclobutyl-6-methoxyphenyl)cyclopropanecarboxylicacid from Example I-51C (20 mg, 0.081 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (31.1 mg, 0.162 mmol) and N,N-dimethylpyridin-4-amine(9.92 mg, 0.081 mmol) in anhydrous N,N-dimethylacetamide (0.4 mL) wasadded quinoline-5-sulfonamide (18.60 mg, 0.089 mmol). After 16 hours,the reaction was diluted with a small piece of ice and quenched with0.25 mL of 1 N aqueous HCl and a precipitate formed. The precipitate waswashed with ice and was taken up in 1.5 mL ofmethanol/dimethylsulfoxide, filtered, and purified by reverse-phasepreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column(30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 9.01 (dd,J=4.2, 1.6 Hz, 1H), 8.73 (dt, J=8.6, 1.3 Hz, 1H), 8.51 (dd, J=7.5, 1.2Hz, 1H), 8.40 (dt, J=8.5, 1.1 Hz, 1H), 8.26 (s, 1H), 7.85 (dd, J=8.5,7.5 Hz, 1H), 7.47 (dd, J=8.8, 4.2 Hz, 1H), 7.39 (t, J=8.1 Hz, 1H), 7.04(d, J=7.8 Hz, 1H), 6.83 (dd, J=8.2, 1.1 Hz, 1H), 3.77 (s, 3H), 3.67 (p,J=8.7 Hz, 1H), 2.35-2.22 (m, 1H), 2.15-2.03 (m, 1H), 2.03-1.94 (m, 1H),1.94-1.78 (m, 2H), 1.78-1.63 (m, 2H), 1.51-1.42 (m, 1H), 1.07-0.90 (m,2H). MS (APCI+) m/z 437 (M+H)⁺.

Example I-521-[2-methoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-52A 1-methoxy-4-(2-methoxypropan-2-yl)benzene

To a solution of 2-(4-methoxyphenyl)propan-2-ol (CAS #7428-99-1) (2.3 g,13.84 mmol) in N,N-dimethylformamide (13 mL) at 0° C. was added sodiumhydride (0.830 g, 20.76 mmol). After 30 minutes, iodomethane (1.298 mL,20.76 mmol) was added and the reaction was stirred at 0° C. for 1 hour.The mixture was quenched via addition of saturated aqueous ammoniumchloride (50 mL) and extracted with ethyl acetate. The crude materialwas purified by chromatography, eluting on 40 g silica gel cartridgewith a gradient of 0-50% ethyl acetate/heptanes over a period of 20minutes to provide the title compound. ¹H NMR (400 MHz, chloroform-d) δppm 7.33 (d, J=8.9 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 3.81 (s, 3H), 3.04(s, 3H), 1.51 (s, 6H). MS (DCI+) m/z 149 (M+H-methanol)⁺.

Example I-52B 2-(3-bromo-4-methoxyphenyl)propan-2-ol

A solution of 1-methoxy-4-(2-methoxypropan-2-yl)benzene from ExampleI-52A (1.75 g, 9.71 mmol) and benzyltrimethylammonium tribromide (4.16g, 10.68 mmol) in tetrahydrofuran (30.3 mL) and degassed water (18.20mL) was stirred at ambient temperature for 5 hours. The volatiles wereremoved in vacuo and the resulting mixture was diluted with 100 mL ofmethyl tert-butyl ether and the organics were concentrated. The crudematerial was purified by chromatography, eluting on 40 g silica gelcartridge with a gradient of 0-50% ethyl acetate/heptanes over a periodof 20 minutes to provide the title compound. ¹H NMR (501 MHz,chloroform-d) δ ppm 7.67 (d, J=2.3 Hz, 1H), 7.39 (dd, J=8.6, 2.3 Hz,1H), 6.86 (d, J=8.5 Hz, 1H), 3.89 (s, 3H), 1.68 (s, 1H), 1.56 (s, 6H).MS (DCI+) m/z 227 (M+H-H₂O)⁺.

Example I-52C 2-bromo-1-methoxy-4-(2-methoxypropan-2-yl)benzene

To a solution of 2-(3-bromo-4-methoxyphenyl)propan-2-ol from ExampleI-52B (0.45 g, 1.836 mmol) in N,N-dimethylformamide (4 mL) at 0° C. wasadded sodium hydride (0.147 g, 3.67 mmol). After 30 minutes, iodomethane(0.230 mL, 3.67 mmol) was added and the reaction was stirred at 0° C.for 3 hours. The mixture was quenched via addition of saturated aqueousammonium chloride (20 mL) and extracted with ethyl acetate. The crudematerial was concentrated, and the residue was purified bychromatography, eluting on a 10 g silica gel cartridge with a gradientof 0-50% ethyl acetate/heptanes over a period of 10 minutes to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.58 (d, J=2.3Hz, 1H), 7.31 (dd, J=8.6, 2.3 Hz, 1H), 6.87 (d, J=8.6 Hz, 1H), 3.90 (s,3H), 3.05 (s, 3H), 1.50 (s, 6H). MS (APCI+) m/z 227 (M+H-methanol)⁺.

Example I-52D Methyl1-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)cyclopropanecarboxylate

To a solution of bis(dibenzylideneacetone)palladium (0.022 g, 0.039mmol) and Q-Phos (pentaphenyl(di-tert-butylphosphino)ferrocene, 0.028 g,0.039 mmol) in tetrahydrofuran (10 mL) at ambient temperature was added2-bromo-1-methoxy-4-(2-methoxypropan-2-yl)benzene from Example I-52C(0.364 mL, 1.956 mmol) in 1 mL tetrahydrofuran followed by a solution offreshly prepared (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (9.78mL, 3.91 mmol). The mixture was stirred at ambient temperature for 16hours. Ethyl acetate and saturated aqueous ammonium chloride was added,and the organic layer was washed with brine and concentrated. Theresidue was purified via chromatography on a 24 g silica gel cartridge,eluting with ethyl acetate in heptane at a 0-50% gradient over a periodof 15 minutes to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.28 (d, J=2.4 Hz, OH), 7.24 (d, J=2.3 Hz, 1H), 6.82(d, J=8.4 Hz, 1H), 3.83 (s, 3H), 3.60 (s, 3H), 3.04 (s, 3H), 1.60 (q,J=4.1 Hz, 2H), 1.51 (s, 6H), 1.11 (q, J=4.1 Hz, 2H). MS (APCI+) m/z 247(M+H-methanol)⁺.

Example I-52E1-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)cyclopropanecarboxylic Acid

Methyl1-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)cyclopropanecarboxylate fromExample I-52D (435 mg, 1.563 mmol) was dissolved in tetrahydrofuran(3.50 mL), methanol (3.50 mL), and water (3.5 mL) and treated withsodium hydroxide (313 mg, 7.81 mmol). The reaction mixture was warmed to45° C. for 2 hours and at 35° C. for 16 hours. The reaction mixture wasconcentrated, cooled in an ice bath and carefully quenched with 1 Naqueous citric acid (about 5.5 mL) until pH ˜5. The resulting slurry wasstirred vigorously and filtered, and the precipitate was washed withwater and dried in a vacuum oven for 16 hours to provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 10.82 (bs, 1H), 7.30-7.24(m, 2H), 6.82 (d, J=8.2 Hz, 1H), 3.84 (s, 3H), 3.02 (s, 3H), 1.65 (q,J=4.1 Hz, 2H), 1.49 (s, 6H), 1.17 (q, J=4.2 Hz, 2H). MS (APCI+) m/z 233(M+H-methanol)⁺.

Example I-52F1-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)-N-(quinolin-5-ylsulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-methoxy-5-(2-methoxypropan-2-yl)phenyl)cyclopropanecarboxylic acidfrom Example I-52E (0.100 g, 0.378 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (0.145 g, 0.757 mmol) and N,N-dimethylpyridin-4-amine(0.051 g, 0.416 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (0.079 g, 0.378 mmol). After 16 hours, thereaction was quenched with 1 mL of aqueous 1 N citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 10 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. Thematerial was triturated with diethyl ether and filtered to provide thetitle compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.55 (s,1H), 9.06 (dd, J=4.2, 1.6 Hz, 1H), 8.97 (dt, J=8.8, 1.2 Hz, 1H), 8.35(d, J=8.5 Hz, 1H), 8.31 (dd, J=7.5, 1.2 Hz, 1H), 7.94 (dd, J=8.4, 7.5Hz, 1H), 7.71 (dd, J=8.8, 4.2 Hz, 1H), 7.24 (dd, J=8.5, 2.4 Hz, 1H),7.07 (d, J=2.4 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 3.35 (s, 3H), 2.95 (s,3H), 1.41 (s, 6H), 1.31 (q, J=4.3 Hz, 2H), 0.95 (q, J=4.5 Hz, 2H). MS(ESI−) m/z 453 (M−H)⁻.

Example I-53N-(1H-indazole-4-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide

A mixture of Example I-49B (50 mg, 0.242 mmol) andN¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine,hydrochloric acid (93 mg, 0.485 mmol) and N,N-dimethylpyridin-4-amine(59.2 mg, 0.485 mmol) in dichloromethane (4 mL) was stirred at ambienttemperature for 30 minutes. 3a,7a-Dihydro-1H-indazole-4-sulfonamide(58.0 mg, 0.291 mmol) was added. The mixture was stirred at 45° C. fortwo hours. The solvent was removed and the residue was dissolved inmethanol (3 mL) and filtered through a syringe filter. The filtrate waspurified via reverse phase HPLC (C18, CH₃CN/H₂O (0.1% trifluoroaceticacid) provided the title compound. ¹H NMR (501 MHz, dimethylsulfoxide-d₆) 6 ppm 11.62 (s, 1H), 10.86 (s, 1H), 7.71 (s, 1H),7.64-7.49 (m, 2H), 7.23 (s, 1H), 7.13 (d, J=8.2 Hz, 1H), 6.96 (d, J=2.3Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.81 (s, 1H), 3.51 (s, 3H), 3.45-3.41(m, 1H), 2.24 (qt, J=8.0, 2.4 Hz, 2H), 2.06 (pd, J=9.2, 2.7 Hz, 2H),1.99-1.90 (m, 1H), 1.85-1.70 (m, 1H), 1.26 (q, J=4.2 Hz, 2H), 0.94 (s,2H). MS (APCI+) m/z 386 (M+H)+. Also obtained was1-(1-(2-methoxy-5-methylphenyl)cyclopropanecarbonyl)-1H-indazole-4-sulfonamide.¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 8.50 (ddd, J=7.5, 1.6, 0.8Hz, 1H), 8.31 (d, J=0.8 Hz, 1H), 7.81-7.73 (m, 2H), 7.64 (s, 2H), 7.13(d, J=2.2 Hz, 1H), 6.94 (dd, J=8.2, 2.0 Hz, 1H), 6.67 (d, J=8.2 Hz, 1H),3.36 (s, 3H), 2.27 (s, 3H), 1.70 (q, J=4.5 Hz, 2H), 1.38 (q, J=4.6 Hz,2H). MS (APCI+) m/z 386 (M+H)⁺.

Example I-541-(5-cyclobutyl-2-methoxyphenyl)-N-(2,3-dihydro-1H-indole-4-sulfonyl)cyclopropane-1-carboxamideExample I-54A Methyl 1-(2-methoxyphenyl)cyclopropanecarboxylate

To a mixture of tris(dibenzylideneacetone)dipalladium(0) (0.086 g, 0.094mmol), 1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (0.133g, 0.187 mmol) and 1-bromo-2-methoxybenzene (2.313 mL, 18.71 mmol) intetrahydrofuran (144 mL) under nitrogen gas,(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (47.8 mL, 22.46 mmol)was added slowly. After the addition, the mixture stirred at ambienttemperature for 16 hours. The mixture was quenched with saturatedaqueous ammonium chloride (20 mL) and 200 mL of ethyl acetate was added.The combined organic layer was washed with saturated aqueous ammoniumchloride and brine, dried over sodium sulfate, filtered, andconcentrated. The residue was purified via chromatography on 120 gsilica gel column, eluting with 0-20% ethyl acetate in heptane toprovide the title compound. MS (APCI+) m/z 207 (M+H)+.

Example I-54B Methyl 1-(5-bromo-2-methoxyphenyl)cyclopropanecarboxylate

A solution of methyl 1-(2-methoxyphenyl)cyclopropanecarboxylate (3.8 g,18.4 mmol) and benzyltrimethylammonium tribromide (7.72 g, 19.80 mmol)in tetrahydrofuran (58.8 mL) and water (35.3 mL) was stirred at ambienttemperature overnight. The solvents were removed under vacuum and theresulting aqueous layer was diluted with 85 mL of methyl tert-butylether. The organics were washed with brine, dried over Na₂SO₄, filteredthrough a pad of silica gel and concentrated to provide the titlecompound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.38 (dd, J=8.7, 2.5 Hz,1H), 7.32 (d, J=2.5 Hz, 1H), 6.77 (d, J=8.7 Hz, 1H), 3.84 (s, 3H), 3.63(s, 3H), 1.64-1.61 (m, 2H), 1.14-1.09 (m, 2H).

Example I-54C 1-(5-bromo-2-methoxyphenyl)cyclopropanecarboxylic Acid

A mixture of Example I-54B (4.88 g, 17.11 mmol) in tetrahydrofuran (35mL) and methanol (35.0 mL) was treated with 3 M aqueous sodium hydroxide(28.5 mL, 86 mmol) and heated at 50° C. for 3 hours and concentrated.The residue was cooled in an ice bath and the pH was carefully adjustedto 1-2 by adding 6 N aqueous HCl. The resulting slurry was stirredvigorously and filtered. The precipitate was washed with water and driedin a vacuum oven overnight to provide the title compound. ¹H NMR (400MHz, dimethyl sulfoxide-d₆) δ ppm 12.06 (s, 1H), 7.37 (dd, J=8.7, 2.5Hz, 1H), 7.28 (d, J=2.6 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 3.74 (s, 3H),1.36 (q, J=4.0 Hz, 2H), 1.01 (q, J=4.1 Hz, 2H).

Example I-54D 1-(5-cyclobutyl-2-methoxyphenyl)cyclopropanecarboxylicAcid

A mixture of Example I-54C (0.8 g, 2.95 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (435 mg) intetrahydrofuran (5 mL) was degassed by bubbling a stream of nitrogenthrough the suspension, and cyclobutylzinc(II) bromide (0.5 M intetrahydrofuran, 12 mL) was added through a syringe filter. The mixturewas stirred at ambient temperature for 2 hours. The solvent was removedand the residue was purified via chromatography on a 25 g silica gelcartridge, eluting with ethyl acetate/methanol (9:1) in heptane at 0-40%gradient to provide the title compound. ¹H NMR (501 MHz, chloroform-d) δppm 7.11 (ddd, J=8.3, 2.3, 0.7 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.80 (d,J=8.3 Hz, 1H), 3.81 (s, 3H), 3.45 (p, J=8.8 Hz, 1H), 2.34-2.25 (m, 2H),2.14-2.04 (m, 2H), 2.03-1.91 (m, 1H), 1.88-1.77 (m, 1H), 1.63 (q, J=4.0Hz, 2H), 1.17 (q, J=4.0 Hz, 2H). MS (ESI+) m/z 246 (M+H)⁺.

Example I-54E1-(5-cyclobutyl-2-methoxyphenyl)-N-(indolin-4-ylsulfonyl)cyclopropanecarboxamide

A mixture of Example I-54D (50 mg, 0.203 mmol) andN-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine,hydrochloric acid (78 mg, 0.406 mmol) and N,N-dimethylpyridin-4-amine(49.6 mg, 0.406 mmol) in dichloromethane (4 mL) was stirred at ambienttemperature for 30 minutes. Indoline-4-sulfonamide (40.7 mg, 0.203 mmol)was added. The mixture was stirred at 40° C. for 2 hours. The solventwas removed and the residue was dissolved in methanol (3 mL) andfiltered through a syringe filter. Purification via reverse phase HPLC(C18, CH₃CN/H₂O (0.1% trifluoroacetic acid), 5-95%, 20 minutes) providedExample I-54E. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 10.83 (s,1H), 7.15 (d, J=8.3 Hz, 1H), 7.07 (t, J=7.9 Hz, 1H), 7.01 (d, J=2.2 Hz,1H), 6.91 (dd, J=16.1, 8.1 Hz, 2H), 6.68 (d, J=7.7 Hz, 1H), 5.93 (s,1H), 3.65 (s, 3H), 3.48-3.43 (m, 3H), 3.14 (t, J=8.7 Hz, 2H), 2.24 (qt,J=8.1, 2.5 Hz, 2H), 2.07 (pd, J=9.1, 2.6 Hz, 2H), 1.93 (dtd, J=11.4,9.8, 8.9, 2.2 Hz, 1H), 1.83-1.73 (m, 1H), 1.35 (q, J=4.3 Hz, 2H), 1.00(s, 2H). MS (trifluoroacetic acid/APCI+) m/z 427 (M+H)⁺. Also providedwas the oxidized product, Example 1-55.

Example I-551-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

The title compound was obtained as a by-product from Example I-54E. ¹HNMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.62 (s, 1H), 10.86 (s, 1H),7.71 (s, 1H), 7.64-7.49 (m, 2H), 7.23 (s, 1H), 7.13 (d, J=8.2 Hz, 1H),6.96 (d, J=2.3 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.81 (s, 1H), 3.51 (s,3H), 3.45-3.41 (m, 1H), 2.24 (qt, J=8.0, 2.4 Hz, 2H), 2.06 (pd, J=9.2,2.7 Hz, 2H), 1.99-1.90 (m, 1H), 1.85-1.70 (m, 1H), 1.26 (q, J=4.2 Hz,2H), 0.94 (s, 2H). MS (APCI+) m/z 427 (M+H)⁺.

Example I-561-(5-cyclobutyl-2-methoxyphenyl)-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide

A mixture of Example I-54D (60 mg, 0.244 mmol) andN¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine,hydrochloric acid (93 mg, 0.487 mmol) and N,N-dimethylpyridin-4-amine(59.5 mg, 0.487 mmol) in dichloromethane (4 mL) was stirred at ambienttemperature for 30 minutes. 1H-Indazole-4-sulfonamide (58.2 mg, 0.292mmol) was added. The mixture was stirred at 45° C. for 2 hours. Thesolvent was removed and the residue was dissolved in methanol (3 mL).Purification via reverse phase HPLC (C18, CH₃CN/H₂O (0.1%trifluoroacetic acid), 5-95%, 20 minutes) provided the title compound.¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 13.60 (s, 1H), 11.28 (s,1H), 8.35 (s, 1H), 7.88 (d, J=8.1 Hz, 1H), 7.68 (d, J=7.0 Hz, 1H), 7.53(t, J=7.8 Hz, 1H), 7.15 (d, J=7.8 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.85(d, J=8.3 Hz, 1H), 3.47 (s, 3H), 3.45-3.42 (m, 3H), 2.29-2.20 (m, 2H),2.13-2.01 (m, 2H), 1.98-1.88 (m, 1H), 1.84-1.74 (m, 1H), 1.25-1.22 (m,2H), 0.96 (s, 2H). MS (ESI+): m/z=426 (M+H). Also provided was1-(1-(5-cyclobutyl-2-methoxyphenyl)cyclopropanecarbonyl)-1H-indazole-4-sulfonamide.¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 8.52-8.48 (m, 1H), 8.31(s, 1H), 7.81-7.74 (m, 2H), 7.64 (s, 2H), 7.17 (d, J=2.2 Hz, 1H), 7.03(dd, J=8.3, 2.2 Hz, 1H), 6.71 (d, J=8.3 Hz, 1H), 3.48 (t, J=8.8 Hz, 1H),3.40 (s, 3H), 2.28 (qq, J=7.5, 2.5 Hz, 2H), 2.09 (pd, J=9.0, 8.6, 2.6Hz, 2H), 1.99-1.90 (m, 1H), 1.82 (tdd, J=12.3, 11.1, 6.9, 2.7 Hz, 1H),1.71 (q, J=4.5 Hz, 2H), 1.39 (q, J=4.6 Hz, 2H). MS (ESI+) m/z 426(M+H)⁺.

Example I-571-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

In a 4 mL vial was added Example I-30C (64 mg, 0.233 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (89 mg, 0.467 mmol), and N,N-dimethylpyridin-4-amine (31.4mg, 0.257 mmol) in dichloromethane (1 mL). Quinoline-5-sulfonamide (53.5mg, 0.257 mmol) was added and the reaction was stirred overnight atambient temperature. The solvent was removed under a stream of nitrogenand the residue was dissolved in methanol. The sample was purified viapreparative reverse phase HPLC/MS method trifluoroacetic acid 1, andsubsequently repurified using method AA3 to afford the title compound.¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) 6 ppm 9.03 (dd,J=8.7, 1.7 Hz, 1H), 8.90 (dd, J=4.2, 1.7 Hz, 1H), 8.24-8.16 (m, 1H),8.07 (s, 1H), 8.05 (s, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.52 (dd, J=8.7, 4.2Hz, 1H), 7.46 (d, J=2.5 Hz, 1H), 2.77 (s, 6H), 1.35-1.30 (m, 2H),0.79-0.72 (m, 2H). MS (APCI) m/z 464.9 (M+H)⁺.

Example I-581-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Example 1-58 was prepared as described in Example 1-62, substituting1-methyl-1H-indole-4-sulfonamide for 2-methylquinoline-8-sulfonamide. ¹HNMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 7.80 (d, J=8.2Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.55 (d, J=3.1 Hz, 1H), 7.31 (t, J=7.9Hz, 1H), 7.22-7.11 (m, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.88 (d, J=8.4 Hz,1H), 6.77 (dd, J=3.0, 0.9 Hz, 1H), 3.87 (s, 3H), 3.53 (s, 3H), 3.43 (p,J=8.6 Hz, 1H), 2.25 (qt, J=7.7, 2.3 Hz, 2H), 2.14-1.71 (m, 4H), 1.26 (q,J=4.3 Hz, 2H), 1.00-0.91 (m, 2H). MS (APCI) m/z 439.0 (M+H)⁺.

Example I-591-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indole-7-sulfonyl)cyclopropane-1-carboxamide

Example 1-59 was prepared as described in Example 1-62, substituting1-methyl-1H-indole-7-sulfonamide for 2-methylquinoline-8-sulfonamide. ¹HNMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 7.92 (dd,J=7.9, 1.2 Hz, 1H), 7.78 (dd, J=7.8, 1.2 Hz, 1H), 7.41 (d, J=3.2 Hz,1H), 7.24-7.10 (m, 2H), 7.05 (d, J=2.2 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H),6.67 (d, J=3.2 Hz, 1H), 3.89 (s, 3H), 3.44 (p, J=8.6 Hz, 1H), 3.34 (s,3H), 2.32-2.17 (m, 2H), 2.16-1.72 (m, 4H), 1.37 (q, J=4.3 Hz, 2H), 1.01(q, J=4.5 Hz, 2H). MS (APCI) m/z 439.0 (M+H)+.

Example I-601-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-1H-indazole-7-sulfonyl)cyclopropane-1-carboxamide

Example 1-60 was prepared as described in Example 1-62, substituting1-methyl-1H-indazole-7-sulfonamide for 2-methylquinoline-8-sulfonamide.¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.29 (s,1H), 8.13 (d, J=8.1 Hz, 1H), 8.02 (d, J=7.4 Hz, 1H), 7.31 (t, J=7.8 Hz,1H), 7.13 (d, J=8.8 Hz, 1H), 7.02 (d, J=2.3 Hz, 1H), 6.80 (d, J=8.4 Hz,1H), 4.12 (s, 3H), 3.50-3.37 (m, 1H), 3.24 (s, 3H), 2.31-2.17 (m, 2H),2.13-1.88 (m, 3H), 1.85-1.74 (m, 1H), 1.38-1.27 (m, 2H), 0.96 (s, 2H).MS (APCI) m/z 440.0 (M+H)⁺.

Example I-611-(5-cyclobutyl-2-methoxyphenyl)-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)cyclopropane-1-carboxamide

Example 1-61 was prepared as described in Example 1-62, substitutingpyrazolo[1,5-a]pyridine-4-sulfonamide for2-methylquinoline-8-sulfonamide. ¹H NMR (400 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.93 (d, J=7.1 Hz, 1H), 8.19 (s, 1H),7.84-7.77 (m, 1H), 7.20-7.02 (m, 2H), 6.95 (dd, J=7.1, 2.3 Hz, 2H), 6.84(d, J=8.4 Hz, 1H), 3.50-3.37 (m, 4H), 2.40-2.17 (m, 2H), 2.12-1.86 (m,3H), 1.86-1.73 (m, 1H), 1.27 (q, J=4.3 Hz, 2H), 1.00-0.91 (m, 2H). MS(APCI) m/z 426.0 (M+H)+.

Example I-621-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-8-sulfonyl)cyclopropane-1-carboxamide

2-Methylquinoline-8-sulfonamide (21.7 mg, 0.10 mmol, 1.0 eq) was weighedinto 4 mL vial. 1-(5-Cyclobutyl-2-methoxyphenyl)cyclopropanecarboxylicacid (20.0 mg, 0.08 mmol, 1.0 eq) from Example I-54D,1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (30.9 mg,0.16 mmol, 2.0 eq) and DMAP (4-dimethylaminopyridine, 10.9 mg, 0.09mmol, 1.1 eq) dissolved dichloromethane (0.5 mL) was added and thereaction was stirred overnight at ambient temperature. The solvent wasremoved under a stream of nitrogen, and the residue was reconstituted indimethylsulfoxide/methanol (1:1). The sample was purified viapreparative reverse phase HPLC/MS method trifluoroacetic acid 7 toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 8.43 (d, J=8.5 Hz, 1H), 8.33 (dd, J=7.4, 1.4 Hz, 1H), 8.30 (dd,J=8.2, 1.4 Hz, 1H), 7.77-7.68 (m, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.20 (dd,J=8.4, 2.3 Hz, 1H), 7.01 (d, J=2.3 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H),3.47-3.40 (m, 1H), 3.34 (s, 3H), 2.57 (s, 3H), 2.31-2.20 (m, 2H),2.12-1.89 (m, 3H), 1.85-1.76 (m, 1H), 1.32-1.21 (m, 2H), 1.02-0.94 (m,2H). MS (APCI+) m/z 451.0 (M+H)⁺.

Example I-631-(5-cyclobutyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of Example I-54D (60 mg, 0.244 mmol) andN′-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (76 mg,0.487 mmol) and N,N-dimethylpyridin-4-amine (59.5 mg, 0.487 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes, and 2-methylquinoline-5-sulfonamide (59.6 mg, 0.268 mmol) wasadded. The mixture was stirred at 45° C. for 2 hours, and stirred at 45°C. for 3 hours. The solvent was removed and the residue was dissolved inmethanol (3 mL) and filtered. Purification via HPLC with trifluoroaceticacid method provided the title compound. ¹H NMR (501 MHz, dimethylsulfoxide-d₆) δ ppm 11.51 (s, 1H), 8.89 (d, J=8.8 Hz, 1H), 8.30-8.20 (m,2H), 7.94-7.86 (m, 1H), 7.61 (d, J=8.9 Hz, 1H), 7.14 (dd, J=8.3, 2.2 Hz,1H), 6.96 (d, J=2.3 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 3.44 (d, J=8.9 Hz,1H), 3.39 (s, 3H), 2.72 (s, 3H), 2.24 (qq, J=7.3, 2.5 Hz, 2H), 2.07 (pd,J=9.0, 2.5 Hz, 2H), 2.00-1.89 (m, 1H), 1.84-1.73 (m, 1H), 1.29-1.20 (m,2H), 0.96 (q, J=4.4 Hz, 2H). MS (ESI+) m/z 451 (M+H)⁺.

Example I-641-(2-methoxy-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of Example I-49B (60 mg, 0.291 mmol) andN¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (90 mg,0.582 mmol) and N,N-dimethylpyridin-4-amine (71.1 mg, 0.582 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. 2-Methylquinoline-5-sulfonamide (71.1 mg, 0.320 mmol) wasadded. The mixture was stirred at 45° C. for 2 hours, and was stirred at45° C. for 3 hours. The solvent was removed and the residue wasdissolved in methanol (3 mL) and was filtered. Purification via HTP withtrifluoroacetic acid method provided the title compound. ¹H NMR (400MHz, dimethyl sulfoxide-d₆) δ ppm 11.49 (s, 1H), 8.87 (d, J=8.9 Hz, 1H),8.28-8.18 (m, 2H), 7.92-7.85 (m, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.12-7.05(m, 1H), 7.00-6.89 (m, 1H), 6.77 (d, J=8.3 Hz, 1H), 3.36 (s, 3H), 2.72(s, 3H), 2.23 (s, 3H), 1.22 (q, J=4.3 Hz, 2H), 0.93 (q, J=4.4 Hz, 2H).MS (ESI+) m/z 411 (M+H)⁺.

Example I-651-[5-(difluoromethoxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-65A Ethyl1-(5-(difluoromethoxy)-2-methoxyphenyl)cyclopropane-1-carboxylate

A solution of Example 1-31E (ethyl1-(5-hydroxy-2-methoxyphenyl)cyclopropanecarboxylate) (30 mg, 0.127mmol) in acetonitrile (0.6 mL) at 0° C. was treated dropwise with 2 MKOH in water (635 μl, 1.270 mmol) over 2 minutes, stirred for 5 minutes,treated with diethyl (bromodifluoromethyl)phosphonate (49.6 μl, 0.279mmol) dropwise over 2 minutes, stirred at 0° C. for 30 minutes, andpartitioned between methyl tert-butyl ether (50 mL) and water (25 mL).The methyl tert-butyl ether was washed with brine, dried (MgSO₄),filtered, concentrated and chromatographed on silica gel, eluting with agradient of 10% to 100% ethyl acetate in heptanes to provide the titlecompound. ¹H NMR (501 MHz, CDCl₃) δ ppm 7.02 (dd, J=3.0, 8.8 Hz, 1H),6.97 (d, J=2.9 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.42 (t, J=74.5 Hz, 1H),4.08 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 1.60 (q, J=4.2 Hz, 2H), 1.14 (t,J=7.1 Hz, 3H), 1.08 (q, J=4.2 Hz, 2H). LC/MS (APCI+) m/z 287 (M+H)+.

Example I-65B1-(5-(difluoromethoxy)-2-methoxyphenyl)cyclopropane-1-carboxylic Acid

In a vial, a solution of Example I-65A (ethyl1-(5-(difluoromethoxy)-2-methoxyphenyl)cyclopropanecarboxylate) (20 mg,0.070 mmol) in tetrahydrofuran (1.5 mL) and methanol (1.5 mL) wastreated with 3 M aqueous NaOH (1.5 mL), stirred at 80° C. for 12 hours,cooled and partitioned between 1 M aqueous HCl (15 mL) and methyltert-butyl ether (50 mL). The methyl tert-butyl ether layer was washedwith brine, dried (MgSO₄), filtered, and concentrated to provide thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.03 (dd, J=2.9, 8.8 Hz,1H), 6.99 (d, J=2.9 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 6.40 (t, J=74.4 Hz,1H), 3.83 (s, 3H), 1.67 (q, J=4.2 Hz, 2H), 1.16 (q, J=4.2 Hz, 2H).

Example I-65C1-[5-(difluoromethoxy)-2-methoxyphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

A solution of Example I-65B(1-(5-(difluoromethoxy)-2-methoxyphenyl)cyclopropanecarboxylic acid(17.2 mg, 0.067 mmol), quinoline-5-sulfonamide) (27.7 mg, 0.133 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (25.5 mg,0.133 mmol) and 4-dimethylaminopyridine (16.28 mg, 0.133 mmol) inN,N-dimethylformamide (0.3 mL) was stirred overnight at ambienttemperature. The mixture was partitioned between methyl tert-butyl ether(50 mL) and 1 M aqueous HCl (15 mL). The methyl tert-butyl ether layerwas washed with 0.2 M aqueous HCl (15 mL), washed with brine, dried(MgSO₄), filtered, concentrated and chromatographed on silica gel,eluting with a gradient of 25% to 100% [200:1:1 ethyl acetate:formicacid:H₂O] in heptanes to provide the title compound. ¹H NMR (501 MHz,dimethyl sulfoxide-d₆) δ ppm 11.69 (s, 1H), 9.05 (dd, J=1.6, 4.2 Hz,1H), 8.94 (dd, J=1.2, 8.7 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 8.31 (d,J=7.4 Hz, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.70 (dd, J=4.1, 8.8 Hz, 1H),7.08 (dd, J=3.0, 8.7 Hz, 1H), 7.08 (t, J=74.7 Hz, 1H), 6.97 (d, J=3.0Hz, 1H), 6.87 (d, J=8.9 Hz, 1H), 3.30 (s, 3H), 1.26 (q, J=4.4 Hz, 2H),0.98 (q, J=4.5 Hz, 2H). LC/MS (APCI+) m/z 449 (M+H)⁺.

Example I-661-(2,6-diethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-66A Methyl 1-(2,6-dihydroxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-7A (methyl1-(2,6-dimethoxyphenyl)cyclopropanecarboxylate) (1.03 g, 4.36 mmol) inCH₂Cl₂ (50 mL) was cooled to −78° C. under nitrogen, treated dropwisewith 1 M BBr₃ in CH₂Cl₂ (4.5 mL, 4.5 mmol), stirred at −78° C. for 40minutes, treated more 1 M BBr₃ in CH₂Cl₂ (4 mL, 4 mmol), stirred at −78°C. for 25 minutes, and treated all at once with 1 M aqueous HCl (25 mL).The mixture was stirred at ambient temperature for 5 minutes and thelayers were separated. The aqueous layer was extracted with CH₂Cl₂ (25mL). The combined CH₂Cl₂ layers were dried (MgSO₄), filtered,concentrated and chromatographed on silica gel, eluting with a gradientof 15% to 50% ethyl acetate in heptanes to provide the title compound.¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 9.05 (s, 2H), 6.82 (t,J=8.1 Hz, 1H), 6.24 (d, J=8.0 Hz, 2H), 3.47 (s, 3H), 1.47 (q, J=4.1 Hz,2H), 1.05 (q, J=4.2 Hz, 2H).

Example I-66B Methyl 1-(2,6-diethoxyphenyl)cyclopropane-1-carboxylate

A solution of Example I-66B (methyl1-(2,6-dihydroxyphenyl)cyclopropanecarboxylate) (25 mg, 0.120 mmol) andethyl iodide (34.0 μl, 0.420 mmol) in N,N-dimethylformamide (0.5 mL) wastreated with 60% dispersion of sodium hydride in mineral oil (14.41 mg,0.360 mmol), stirred at ambient temperature for 20 minutes, andpartitioned between methyl tert-butyl ether (30 mL) and 1 M aqueous HCl(10 mL). The methyl tert-butyl ether layer was washed with water (5 mL),washed with brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel, eluting with a gradient of 5% to 30%ethyl acetate in heptanes to provide the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 7.16 (t, J=8.3 Hz, 1H), 6.50 (d, J=8.3 Hz, 2H), 4.02(q, J=7.0 Hz, 4H), 3.58 (s, 3H), 1.66 (q, J=4.3 Hz, 2H), 1.37 (t, J=7.0Hz, 6H), 1.16 (q, J=4.3 Hz, 2H).

Example I-66C 1-(2,6-diethoxyphenyl)cyclopropane-1-carboxylic Acid

In a vial, a solution of Example I-66B (methyl1-(2,6-diethoxyphenyl)cyclopropanecarboxylate) (25 mg, 0.095 mmol) intetrahydrofuran (1.5 mL) and methanol (1.5 mL) was treated with 3 Maqueous NaOH (1.5 mL), stirred at 80° C. for 12 hours, cooled andpartitioned between 1 M aqueous HCl (15 mL) and methyl tert-butyl ether(50 mL). The methyl tert-butyl ether layer was washed with brine, dried(MgSO₄), filtered, and concentrated to provide the title compound. ¹HNMR (400 MHz, CDCl₃) δ ppm 7.15 (t, J=8.3 Hz, 1H), 6.49 (d, J=8.3 Hz,2H), 4.03 (q, J=7.0 Hz, 4H), 1.71 (q, J=4.3 Hz, 2H), 1.39 (t, J=7.0 Hz,6H), 1.22 (q, J=4.4 Hz, 2H).

Example I-66D1-(2,6-diethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

A solution of Example I-66C,1-(2,6-diethoxyphenyl)cyclopropanecarboxylic acid (22.8 mg, 0.091 mmol),quinoline-5-sulfonamide (37.9 mg, 0.182 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34.9 mg,0.182 mmol) and 4-dimethylaminopyridine (22.26 mg, 0.182 mmol) inN,N-dimethylformamide (0.3 mL) was stirred overnight at ambienttemperature. The mixture was partitioned between methyl tert-butyl ether(50 mL) and 1 M aqueous HCl (15 mL). The methyl tert-butyl ether layerwas washed with 0.2 M aqueous HCl (15 mL), washed with brine, dried(MgSO₄), filtered, concentrated and chromatographed on silica gel,eluting with a gradient of 25% to 100% [200:1:1 ethyl acetate:formicacid:H₂O] in heptanes to provide the title compound. ¹H NMR (501 MHz,dimethyl sulfoxide-d₆) δ ppm 11.21 (s, 1H), 9.04 (dd, J=1.6, 4.2 Hz,1H), 9.00-8.97 (m, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.30 (dd, J=1.3, 7.5 Hz,1H), 7.92 (dd, J=7.4, 8.4 Hz, 1H), 7.69 (dd, J=4.1, 8.8 Hz, 1H), 7.18(t, J=8.3 Hz, 1H), 6.52 (d, J=8.3 Hz, 2H), 3.83 (q, J=6.9 Hz, 4H), 1.41(q, J=4.3 Hz, 2H), 0.98-0.93 (m, 8H). LC/MS (APCI+) m/z 441 (M+H)⁺.

Example I-67N-(2-aminoquinoline-5-sulfonyl)-1-(5-cyclobutyl-2-methoxyphenyl)cyclopropane-1-carboxamide

In a 4 mL vial was added1-(5-cyclobutyl-2-methoxyphenyl)cyclopropanecarboxylic acid (20 mg,0.081 mmol) from Example I-54D,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (31.1 mg, 0.162 mmol), and N,N-dimethylpyridin-4-amine(10.91 mg, 0.089 mmol) in dichloromethane (DCM) (0.5 mL). tert-ButylN-tert-butoxycarbonyl-N-(5-sulfamoyl-2-quinolyl)carbamate (37.8 mg,0.089 mmol) was added. The reaction was stirred overnight at ambienttemperature. The solvent was removed under a stream of nitrogen.2,2,2-Trifluoroacetic acid (1 mL, 12.98 mmol) was added and the reactionwas stirred at ambient temperature for 1 hour. The solvent was removedunder a stream of nitrogen, and the residue reconstituted in dimethylsulfoxide/methanol and purified on preparative reverse phase HPLC/MSmethod trifluoroacetic acid 7. ¹H NMR (400 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.84 (d, J=9.8 Hz, 1H), 8.06-8.00 (m,1H), 7.93-7.87 (m, 2H), 7.21-7.08 (m, 2H), 6.96 (d, J=2.2 Hz, 1H), 6.85(d, J=8.4 Hz, 1H), 3.51 (s, 3H), 3.47-3.32 (m, 1H), 2.29-2.16 (m, 2H),2.11-1.83 (m, 3H), 1.83-1.70 (m, 1H), 1.30-1.19 (m, 2H), 1.02-0.92 (m,2H). MS (APCI) m/z 452.0 (M+H)⁺.

Example I-681-(5-cyclopropyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

A solution of Example I-12B(1-(5-cyclopropyl-2-methoxy)phenyl)cyclopropanecarboxylic acid) (21.4mg, 0.092 mmol), 2-methylquinoline-5-sulfonamide (41.0 mg, 0.184 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.3 mg,0.184 mmol) and 4-dimethylaminopyridine (22.51 mg, 0.184 mmol) inN,N-dimethylformamide (0.3 mL) was stirred overnight at ambienttemperature. The mixture was partitioned between methyl tert-butyl ether(50 mL) and 1 M aqueous HCl (15 mL). The methyl tert-butyl ether layerwas washed with 0.2 M aqueous HCl (15 mL), washed with brine, dried(MgSO₄), filtered, concentrated and chromatographed on silica gel,eluting with a gradient of 25% to 100% [200:1:1 ethyl acetate:formicacid:H₂O] in heptanes to provide the title compound. ¹H NMR (501 MHz,dimethyl sulfoxide-d₆) δ ppm 11.50 (bs, 1H), 8.85 (d, J=8.8 Hz, 1H),8.23-8.19 (m, 2H), 7.86 (t, J=7.9 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H), 6.94(dd, J=2.3, 8.4 Hz, 1H), 6.84 (d, J=2.3 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H),3.35 (s, 3H), 2.71 (s, 3H), 1.84 (tt, J=5.1, 8.4 Hz, 1H), 1.21 (q, J=4.3Hz, 2H), 0.93 (q, J=4.4 Hz, 2H), 0.89-0.84 (m, 2H), 0.63-0.58 (m, 2H).LC/MS (APCI+) m/z 437 (M+H)⁺.

Example I-691-(5-ethoxy-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example 1-69 was prepared as described in Example I-34B, substituting1-(5-ethoxy-2-methoxyphenyl)cyclopropane-1-carboxylic acid from ExampleI-31G for Example I-34B, and 2-methylquinoline-5-sulfonamide forquinoline-5-sulfonamide. ¹H NMR (500 MHz, dimethyl sulfoxide-d₆:D₂O=9:1(v/v)) δ ppm 8.91-8.76 (m, 1H), 8.24 (ddd, J=7.5, 5.6, 1.1 Hz, 2H), 7.90(dd, J=8.4, 7.5 Hz, 1H), 7.61 (d, J=8.9 Hz, 1H), 6.88-6.73 (m, 2H), 6.69(d, J=2.9 Hz, 1H), 3.96 (q, J=6.9 Hz, 2H), 3.31 (s, 3H), 2.73 (s, 3H),1.31 (t, J=7.0 Hz, 3H), 1.21 (q, J=2.8 Hz, 2H), 0.96 (q, J=4.5 Hz, 2H).MS (APCI) m/z 441.0 (M+H)⁺.

Example I-701-(5-tert-butyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example 1-70 was prepared as described in Example I-34B, substituting2-methylquinoline-5-sulfonamide for quinoline-5-sulfonamide. ¹H NMR (501MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) 6 ppm 8.86 (d, J=8.9 Hz, 1H),8.20 (t, J=7.7 Hz, 2H), 7.87 (t, J=7.9 Hz, 1H), 7.59 (d, J=8.9 Hz, 1H),7.26 (dd, J=8.6, 2.5 Hz, 1H), 7.08 (d, J=2.5 Hz, 1H), 6.79 (d, J=8.7 Hz,1H), 3.36 (s, 3H), 2.72 (s, 3H), 1.42-1.14 (m, 11H), 0.98-0.88 (m, 2H).MS (APCI) m/z 453.0 (M+H)⁺.

Example I-711-[2-methoxy-5-(propan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example 1-71 was prepared as described in Example I-35B, substituting2-methylquinoline-5-sulfonamide for quinoline-5-sulfonamide. ¹H NMR (400MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) 6 ppm 8.93 (d, J=9.0 Hz, 1H),8.34-8.18 (m, 2H), 7.94 (t, J=8.0 Hz, 1H), 7.68 (d, J=9.0 Hz, 1H), 7.13(dd, J=8.4, 2.3 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H),3.35 (s, 3H), 2.86-2.67 (m, 4H), 1.25 (q, J=2.8 Hz, 2H), 1.16 (d, J=6.9Hz, 6H), 0.96 (q, J=4.5 Hz, 2H). MS (APCI) m/z 439.0 (M+H)+.

Example I-721-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example 1-72 was prepared as described in Example 1-57, substituting2-methylquinoline-5-sulfonamide for quinoline-5-sulfonamide. ¹H NMR (501MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) 6 ppm 7.21 (dd, J=8.3, 7.5 Hz,1H), 7.10-6.99 (m, 2H), 6.91-6.85 (m, 1H), 6.84-6.78 (m, 1H), 6.73 (dd,J=7.4, 1.9 Hz, 1H), 3.77 (s, 3H), 3.18 (t, J=5.5 Hz, 2H), 2.85 (t, J=6.4Hz, 2H), 2.19 (s, 3H), 1.78 (p, J=6.1 Hz, 2H), 1.66-1.47 (m, 2H),1.17-0.95 (m, 2H). MS (APCI) m/z 478.9 (M+H)⁺.

Example I-731-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-73A Methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate

To a solution of Q-Phos (pentaphenyl(di-tert-butylphosphino)ferrocene,0.076 g, 0.107 mmol) and bis(dibenzylideneacetone)palladium (0.061 g,0.107 mmol) in tetrahydrofuran (25 mL) at ambient temperature was added1-bromo-4-methoxybenzene (0.669 mL, 5.35 mmol) followed by a solution offreshly-prepared (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (24.87mL, 10.69 mmol). The mixture was stirred at ambient temperature for 16hours. Ethyl acetate and saturated aqueous ammonium chloride were added.The organic layer was washed with brine and was concentrated. Theresidue was purified via chromatography on a 24 g silica gel cartridge,eluting with ethyl acetate in heptane at 0-30% gradient in a period of15 minutes to provide the title compound. ¹H NMR (400 MHz, chloroform-d)δ ppm 7.29-7.22 (m, 2H), 6.88-6.81 (m, 2H), 3.80 (s, 3H), 3.62 (s, 3H),1.57 (q, J=3.9 Hz, 2H), 1.15 (q, J=3.9 Hz, 2H). MS (APCI+) m/z 207(M+H)⁺.

Example I-73B Methyl 1-(3-bromo-4-methoxyphenyl)cyclopropanecarboxylate

A solution of methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate fromExample I-73A (0.702 g, 3.40 mmol) and benzyltrimethylammoniumtribromide (2.65 g, 6.81 mmol) in tetrahydrofuran (10 mL) and degassedwater (6.00 mL) was stirred at ambient temperature for 40 hours. Themixture was diluted with 100 mL of diethyl ether, and filtered. Theorganic layer was separated and concentrated in vacuo. The crude residuewas purified by chromatography, eluting on a 24 g silica gel cartridgewith 100% dichloromethane to provide crude product which was purifiedfurther on a 10 g silica gel cartridge with a gradient of 0-4%methanol/dichloromethane over a period of 15 minutes to provide thetitle compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.52 (d, J=2.2 Hz,1H), 7.24 (dd, J=8.4, 2.2 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 3.89 (s, 3H),3.63 (s, 3H), 1.59 (q, J=4.0 Hz, 2H), 1.15 (q, J=4.0 Hz, 2H). MS (ESI+)m/z 285 (M+H)⁺.

Example I-73C (1-(3-bromo-4-methoxyphenyl)cyclopropyl)methanol

To a solution of methyl1-(3-bromo-4-methoxyphenyl)cyclopropanecarboxylate from Example I-73B(0.7 g, 2.455 mmol) in dichloromethane (7.0 mL) at 0° C. was addeddiisobutylaluminium hydride in dichloromethane (7.36 mL, 7.36 mmol). Thereaction was stirred at 0° C. for 30 minutes and was quenched with 20 mL1 N aqueous citric acid. The organic layer was separated andconcentrated in vacuo. The residue was purified on a 10 g silica gelcartridge with a gradient of 0-4% methanol/dichloromethane over a periodof 15 minutes to provide the title compound. ¹H NMR (501 MHz,chloroform-d) δ ppm 7.55 (d, J=2.2 Hz, 1H), 7.28 (dd, J=8.4, 2.2 Hz,1H), 6.84 (d, J=8.4 Hz, 1H), 3.88 (s, 3H), 3.62 (d, J=5.6 Hz, 2H), 1.39(t, J=6.1 Hz, 1H), 0.86-0.79 (m, 4H). MS (ESI+) m/z 239 (M+H-H₂O)⁺.

Example I-73D 2-bromo-1-methoxy-4-(1-(methoxymethyl)cyclopropyl)benzene

To a solution of (1-(3-bromo-4-methoxyphenyl)cyclopropyl)methanol fromExample I-73C (525 mg, 2.042 mmol) in N,N-dimethylformamide (4 mL) at 0°C. was added sodium hydride (163 mg, 4.08 mmol). After 30 minutes,iodomethane (0.255 mL, 4.08 mmol) was added and the reaction was stirredat 0° C. for 2 hours. The mixture was quenched via addition of saturatedaqueous ammonium chloride (50 mL) and extracted with ethyl acetate. Theorganic layer was concentrated, and the crude material was purified bychromatography, eluting on a 10 g silica gel cartridge with a gradientof 0-50% ethyl acetate/heptanes over a period of 10 minutes to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.51 (d, J=2.2Hz, 1H), 7.24 (dd, J=8.4, 2.2 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 3.87 (s,3H), 3.42 (s, 2H), 3.30 (s, 3H), 0.83 (s, 4H). MS (APCI+) m/z 239(M+H-methanol)⁺.

Example I-73E Methyl1-(2-methoxy-5-(1-(methoxymethyl)cyclopropyl)phenyl)cyclopropanecarboxylate

To a solution of Q-Phos (pentaphenyl(di-tert-butylphosphino)ferrocene,0.028 g, 0.039 mmol) and bis(dibenzylideneacetone)palladium (0.022 g,0.039 mmol) in tetrahydrofuran (10 mL) at ambient temperature was added2-bromo-1-methoxy-4-(1-(methoxymethyl)cyclopropyl)benzene from ExampleI-73D (0.53 g, 1.955 mmol) followed by a solution of freshly prepared(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (9.09 mL, 3.91 mmol).The mixture was stirred at ambient temperature for 3 days. Ethyl acetateand saturated aqueous ammonium chloride was added, and the organic layerwas washed with brine and concentrated. The residue was purified viachromatography on a 24 g silica gel cartridge, eluting with an ethylacetate in heptane at 0-60% gradient for a period of 15 minutes toprovide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.23(dd, J=8.4, 2.4 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H),3.80 (s, 3H), 3.59 (s, 3H), 3.43 (s, 2H), 3.30 (s, 3H), 1.58 (q, J=4.1Hz, 2H), 1.10 (q, J=4.1 Hz, 2H), 0.86-0.79 (m, 4H). MS (APCI+) m/z 259(M+H-methanol)+.

Example I-73F1-(2-methoxy-5-(1-(methoxymethyl)cyclopropyl)phenyl)cyclopropanecarboxylicAcid

Methyl1-(2-methoxy-5-(1-(methoxymethyl)cyclopropyl)phenyl)cyclopropanecarboxylatefrom Example I-73E (340 mg, 1.171 mmol) was dissolved in tetrahydrofuran(2.6 mL), methanol (2.60 mL) and water (2.60 mL) and then treated withsodium hydroxide (234 mg, 5.85 mmol). The reaction mixture was stirredat 35° C. overnight. The reaction was concentrated, cooled in an icebath and carefully quenched with 1 N aqueous citric acid (about 6 mL)until pH ˜5. The resulting slurry was stirred vigorously and filtered.The material was washed with water and dried in a vacuum oven overnightto provide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.23(dd, J=8.4, 2.3 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H),3.81 (s, 3H), 3.42 (s, 2H), 3.29 (s, 3H), 1.63 (q, J=4.0 Hz, 2H), 1.16(q, J=4.1 Hz, 2H), 0.83-0.80 (m, 4H). MS (ESI−) m/z 275 (M−H).

Example I-73G1-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-methoxy-5-(1-(methoxymethyl)cyclopropyl)phenyl)cyclopropanecarboxylicacid from Example I-73F (80 mg, 0.290 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (111 mg, 0.579 mmol) and N,N-dimethylpyridin-4-amine (38.9mg, 0.318 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (60.3 mg, 0.290 mmol). After 16 hours, thereaction was quenched with 1 mL of aqueous 1 N citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 10 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. Thematerial was triturated with diethyl ether and filtered to provide thetitle compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.52 (s,1H), 9.05 (dd, J=4.2, 1.6 Hz, 1H), 9.01-8.95 (m, 1H), 8.34 (d, J=8.5 Hz,1H), 8.30 (d, J=7.4 Hz, 1H), 7.93 (t, J=7.9 Hz, 1H), 7.70 (dd, J=8.8,4.2 Hz, 1H), 7.17 (dd, J=8.4, 2.3 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.75(d, J=8.5 Hz, 1H), 3.40 (s, 2H), 3.32 (s, 3H), 3.21 (s, 3H), 1.27 (q,J=4.3 Hz, 2H), 0.93 (s, 2H), 0.80-0.76 (m, 4H). MS (APCI+) m/z 467(M+H)⁺.

Example I-741-{2-methoxy-5-[1-(methoxymethyl)cyclopropyl]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-methoxy-5-(1-(methoxymethyl)cyclopropyl)phenyl)cyclopropanecarboxylicacid from Example I-73F (80 mg, 0.290 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (111 mg, 0.579 mmol) and N,N-dimethylpyridin-4-amine (38.9mg, 0.318 mmol) in anhydrous dichloromethane (1 mL) was added2-methylquinoline-5-sulfonamide (64.3 mg, 0.290 mmol). After 16 hours,the reaction was quenched with 1 mL of aqueous 1 N citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 10 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. Thematerial was triturated with diethyl ether and filtered to provide thetitle compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d) δ ppm 11.47 (s,1H), 8.85 (d, J=8.9 Hz, 1H), 8.21 (t, J=8.5 Hz, 2H), 7.86 (t, J=8.0 Hz,1H), 7.58 (d, J=8.9 Hz, 1H), 7.17 (dd, J=8.5, 2.3 Hz, 1H), 6.96 (d,J=2.3 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 3.40 (s, 2H), 3.33 (s, 3H), 3.21(s, 3H), 2.71 (s, 3H), 1.27 (q, J=4.3 Hz, 2H), 0.92 (s, 2H), 0.84-0.72(m, 4H). MS (APCI+) m/z 481 (M+H)⁺.

Example I-751-(2-methoxyquinolin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-75A 1-(2-methoxyquinolin-3-yl)cyclopropanecarboxylic Acid

The title compound was prepared as described in the procedures describedin Example I-3A to Example I-3D, substituting3-(bromomethyl)-2-methoxyquinoline for3-(bromomethyl)-5-cyclobutyl-2-methoxypyridine.

Example I-75B1-(2-methoxyquinolin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of Example I-75A (45 mg, 0.185 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (57.4 mg,0.370 mmol) and N,N-dimethylpyridin-4-amine (45.2 mg, 0.370 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. 2-Methylquinoline-5-sulfonamide (41.1 mg, 0.185 mmol) wasadded. The mixture was stirred at 45° C. for 2 hours, and concentrated.The residue was dissolved in methanol (3 mL) and filtered. Purificationvia reverse phase HPLC (C18, CH₃CN/H₂O (0.1% trifluoroacetic acid),5-95%, 20 minutes) provided the title compound. ¹H NMR (400 MHz,dimethyl sulfoxide-d₆) δ ppm 11.86 (s, 1H), 8.82 (d, J=8.9 Hz, 1H), 8.27(dd, J=7.9, 4.2 Hz, 2H), 8.11 (s, 1H), 7.96-7.89 (m, 1H), 7.87 (dd,J=8.1, 1.4 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.67 (ddd, J=8.4, 6.8, 1.4Hz, 1H), 7.61 (d, J=8.9 Hz, 1H), 7.45 (t, J=7.4 Hz, 1H), 3.62 (s, 3H),2.74 (s, 3H), 1.33 (q, J=4.2 Hz, 2H), 1.13 (q, J=4.3 Hz, 2H). MS (ESI+)m/z 448.2 (M+H)⁺.

Example I-761-(2-methoxyquinolin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of 1-(2-methoxyquinolin-3-yl)cyclopropanecarboxylic acid(Example I-75A, 30 mg, 0.123 mmol) andNi-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (38.3 mg,0.247 mmol) and N,N-dimethylpyridin-4-amine (30.1 mg, 0.247 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. Quinoline-5-sulfonamide (25.7 mg, 0.123 mmol) was added. Themixture was stirred at 45° C. for 3 hours, and concentrated. The residuewas dissolved in methanol (3 mL) and filtered. Purification via reversephase HPLC (C18, CH₃CN/H₂O (0.1% trifluoroacetic acid), 5-95%, 20minutes), followed by purification through a 4 g silica gel cartridgeprovided the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.90 (d, J=58.4 Hz, 1H), 9.07 (dd, J=4.2, 1.5 Hz, 1H), 8.91 (dd,J=8.9, 1.4 Hz, 1H), 8.36 (dd, J=11.8, 7.8 Hz, 2H), 8.11 (s, 1H),8.00-7.94 (m, 1H), 7.87 (dd, J=8.1, 1.4 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H),7.73-7.63 (m, 2H), 7.45 (t, J=7.4 Hz, 1H), 3.58 (s, 3H), 1.34 (q, J=4.2Hz, 2H), 1.13 (q, J=4.3 Hz, 2H). MS (ESI+) m/z 434 (M+H)⁺.

Example I-771-{5-methyl-2-[(propan-2-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-77A 2-bromo-1-isopropoxy-4-methylbenzene

To 2-bromo-4-methylphenol [CAS #6627-56-0] (2 g, 10.69 mmol) inN,N-dimethylformamide (10 mL) was added potassium carbonate (2.96 g,21.39 mmol) at ambient temperature. The mixture was stirred at ambienttemperature for 10 minutes. 2-lodopropane (2.135 mL, 21.39 mmol) wasadded dropwise, and the mixture stirred at 50° C. for overnight. To thereaction mixture was added ethyl acetate (20 mL). The mixture wasfiltered, and the material was washed with ethyl acetate (10 mL×2). Thecombined organics were washed with water and brine, dried over MgSO₄,filtered, and concentrated. The residue was purified via chromatographyon a 24 g silica gel cartridge, eluting with ethyl acetate in heptane at0-40% gradient to provide 2-bromo-1-isopropoxy-4-methylbenzene. ¹H NMR(400 MHz, chloroform-d) δ ppm 7.35 (dd, J=2.1, 0.8 Hz, 1H), 7.01 (ddd,J=8.3, 2.1, 0.8 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 4.47 (hept, J=6.1 Hz,1H), 2.26 (s, 3H), 1.35 (d, J=6.1 Hz, 6H). MS (APCI+) m/z 229 (M+H)+.

Example I-77B Methyl1-(2-isopropoxy-5-methylphenyl)cyclopropane-1-carboxylate

To Example I-77A (2.10 g, 9.17 mmol) in 10 mL of dry tetrahydrofuran wasadded Q-Phos (pentaphenyl(di-tert-butylphosphino)ferrocene, 0.130 g,0.183 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.168 g, 0.183mmol). A solution of freshly-prepared(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (45.8 mL, 18.33 mmol)in tetrahydrofuran (0.40 mmol/mL, 46 mL) was added via a stainless steelcannula under nitrogen pressure. The mixture was stirred at ambienttemperature for 20 minutes. Ethyl acetate and saturated aqueous NH₄Clwere added. The organic layer was washed with brine and wasconcentrated. The residue was purified via chromatography on a 40 gsilica gel cartridge, eluting with ethyl acetate in heptane using 0-50%gradient to provide the title compound. MS (APCI+) m/z 249 (M+H)⁺.

Example I-77C 1-(2-isopropoxy-5-methylphenyl)cyclopropanecarboxylic Acid

Example I-77B (2.0 g, 8.05 mmol) and lithium hydroxide (1.93 g, 81 mmol)were added to methanol (10 mL) and water (3 mL). The mixture was stirredat 45° C. overnight. The mixture was concentrated to half its volume andthe pH was adjusted to between 0-1 by adding 2 M aqueous HCl. Themixture was extracted with dichloromethane (20 mL×3) and the combinedorganics were washed with brine, dried over MgSO₄, filtered, andconcentrated to provide the title compound. ¹H NMR (500 MHz,chloroform-d) δ ppm 7.09-6.96 (m, 2H), 6.79-6.68 (m, 1H), 4.53 (pd,J=6.1, 0.6 Hz, 1H), 2.25 (t, J=0.7 Hz, 3H), 1.60 (q, J=4.1 Hz, 2H), 1.30(d, J=6.0 Hz, 6H), 1.13 (q, J=4.1 Hz, 2H). MS (APCI+) m/z 235 (M+H)⁺.

Example I-77D1-(2-isopropoxy-5-methylphenyl)-N-(quinolin-5-ylsulfonyl)cyclopropanecarboxamide

A mixture of Example I-77C (100 mg, 0.427 mmol),Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (133 mg,0.854 mmol) and N,N-dimethylpyridin-4-amine (104 mg, 0.854 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. Quinoline-5-sulfonamide (89 mg, 0.427 mmol) was added. Themixture was stirred at 45° C. for 3 hours, and concentrated. The residuewas dissolved in methanol (3 mL) and filtered. Purification via reversephase HPLC (C18, CH₃CN/H₂O (0.1% trifluoroacetic acid), 5-95%, 20minutes), followed by purification through a 4 g silica gel cartridge,eluting with methanol in ethyl acetate at 0-10% gradient to get rid ofsalts, provided the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.48 (s, 1H), 9.10-8.96 (m, 2H), 8.32 (ddd, J=7.3,6.1, 1.1 Hz, 2H), 7.92 (dd, J=8.4, 7.5 Hz, 1H), 7.70 (dd, J=8.7, 4.2 Hz,1H), 7.02 (dd, J=8.3, 2.2 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H), 6.76 (d,J=8.3 Hz, 1H), 4.33 (hept, J=6.1 Hz, 1H), 2.21 (s, 3H), 1.24 (q, J=4.4Hz, 2H), 0.92 (q, J=4.4 Hz, 2H), 0.89 (d, J=6.0 Hz, 6H). MS (ESI+) m/z425 (M+H)⁺.

Example I-781-{5-methyl-2-[(propan-2-yl)oxy]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

A mixture of Example I-77C (100 mg, 0.427 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diamine (133 mg,0.854 mmol) and N,N-dimethylpyridin-4-amine (104 mg, 0.854 mmol) indichloromethane (2 mL) was stirred at ambient temperature for 30minutes. 2-Methylquinoline-5-sulfonamide (95 mg, 0.427 mmol) was added.The mixture was stirred at 45° C. for 2 hours, and was concentrated. Theresidue was dissolved in methanol (2 mL) and the mixture was filtered.Purification via reverse phase HPLC (C18, CH₃CN/H₂O (0.1%trifluoroacetic acid), 5-95%, 20 minutes), followed by purificationthrough a 4 g silica gel cartridge, eluting with methanol in ethylacetate at 0-10% gradient to get rid of salts, provided the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.45 (s, 1H),8.95 (d, J=8.9 Hz, 1H), 8.32-8.17 (m, 2H), 7.88 (dd, J=8.5, 7.4 Hz, 1H),7.63 (d, J=8.9 Hz, 1H), 7.03 (dd, J=8.5, 2.2 Hz, 1H), 6.92 (d, J=2.3 Hz,1H), 6.77 (d, J=8.3 Hz, 1H), 4.36 (hept, J=6.0 Hz, 1H), 2.72 (s, 3H),2.56 (s, 3H), 2.21 (s, 3H), 1.23 (q, J=4.3 Hz, 2H), 0.98-0.83 (m, 8H).MS (ESI+) m/z 439 (M+H)⁺.

Example I-79N-(2-aminoquinoline-5-sulfonyl)-1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxamide

Example 1-79 was prepared as described in Example 1-67, substituting1-(2-methoxy-5-methylphenyl)cyclopropane-1-carboxylic acid from ExampleI-44B for 1-(5-cyclobutyl-2-methoxyphenyl)cyclopropanecarboxylic acid.¹H NMR (501 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.83 (d,J=9.8 Hz, 1H), 8.02 (dd, J=6.4, 2.4 Hz, 1H), 7.92-7.84 (m, 2H), 7.15 (d,J=9.7 Hz, 1H), 7.12-7.06 (m, 1H), 6.96 (d, J=2.2 Hz, 1H), 6.82 (d, J=8.2Hz, 1H), 3.51 (s, 3H), 2.24 (s, 3H), 1.24 (q, J=4.2 Hz, 2H), 0.95 (q,J=4.4 Hz, 2H). MS (APCI) m/z 412.0 (M+H)⁺.

Example I-801-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Quinoline-5-sulfonamide (22.6 mg, 0.11 mmol, 1.2 eq) was weighed into 4mL vial. 1-(4-Cyclobutyl-2,6-dimethoxyphenyl)cyclopropanecarboxylic acid(Example I-86D, 25 mg, 0.09 mmol, 1.0 eq), 4-dimethylaminopyridine (12.2mg, 0.10 mmol, 1.1 eq) and EDC HCl(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl, 34.4 mg, 0.18 mmol,2.0 eq) were all combined and dissolved in 0.4 mL dichloromethane. Thisstock solution was added to the 4 mL vial containingquinoline-5-sulfonamide. The reaction was stirred overnight at ambienttemperature. The solvent was removed under a stream of nitrogen, and theresidue was dissolved in dimethyl sulfoxide/methanol. The mixture waspurified via preparative reverse phase HPLC/MS method trifluoroaceticacid 8 to provide the title compound. ¹H NMR (501 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 9.10-8.99 (m, 2H), 8.40-8.28 (m, 2H),7.95 (dd, J=8.4, 7.4 Hz, 1H), 7.76 (dd, J=8.8, 4.2 Hz, 1H), 6.41-6.33(m, 2H), 3.77 (s, 3H), 3.63 (s, 3H), 3.41 (p, J=8.9 Hz, 1H), 2.17-2.06(m, 1H), 2.06-1.92 (m, 1H), 1.69-1.31 (m, 6H), 0.94-0.86 (m, 2H). MS(APCI) m/z 467.0 (M+H)⁺.

Example I-81N-(2-aminoquinoline-5-sulfonyl)-1-(2,5-dimethylphenyl)cyclopropane-1-carboxamide

Example I-81 was prepared as described in Example 1-67, substituting1-(2,5-dimethylphenyl)cyclopropane-1-carboxylic acid [CAS #1260676-68-3]for 1-(5-cyclobutyl-2-methoxyphenyl)cyclopropanecarboxylic acid. ¹H NMR(400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.84 (d, J=9.8 Hz,1H), 8.01 (q, J=4.6 Hz, 1H), 7.93-7.83 (m, 2H), 7.14 (d, J=9.8 Hz, 1H),7.04-6.94 (m, 3H), 2.26 (s, 3H), 1.93 (s, 3H), 1.37 (q, J=3.6 Hz, 2H),1.00 (q, J=3.9 Hz, 2H). MS (APCI) m/z 396.1 (M+H)⁺.

Example I-821-(2-ethoxy-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of 1-(2-ethoxy-5-methylphenyl)cyclopropanecarboxylic acid(50 mg, 0.227 mmol) from Example I-89B,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (87 mg, 0.454 mmol) and N,N-dimethylpyridin-4-amine (30.5mg, 0.250 mmol) in anhydrous dichloromethane (0.75 mL) was addedquinoline-5-sulfonamide (47.3 mg, 0.227 mmol). After 16 hours, thereaction was quenched with 1 mL of aqueous 1N citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 10 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. The crudematerial was triturated with methanol (0.75 mL), filtered to provide thetitle compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) 6 ppm 11.51 (s,1H), 9.04 (dd, J=4.2, 1.6 Hz, 1H), 8.96 (dt, J=8.8, 1.2 Hz, 1H), 8.32(t, J=8.2 Hz, 2H), 7.92 (d, J=8.0 Hz, 1H), 7.68 (dd, J=8.8, 4.2 Hz, 1H),7.08-7.01 (m, 1H), 6.94 (d, J=2.2 Hz, 1H), 6.73 (d, J=8.2 Hz, 1H), 3.61(q, J=6.9 Hz, 2H), 2.23 (s, 3H), 1.22 (q, J=4.3 Hz, 2H), 0.92 (q, J=4.4Hz, 2H), 0.76 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 411 (M+H)⁺.

Example I-831-(2-ethoxy-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of 1-(2-ethoxy-5-methylphenyl)cyclopropanecarboxylic acid(50 mg, 0.227 mmol) from Example I-89B,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (87 mg, 0.454 mmol) and N,N-dimethylpyridin-4-amine (30.5mg, 0.250 mmol) in anhydrous dichloromethane (0.75 mL) was added2-methylquinoline-5-sulfonamide (50.5 mg, 0.227 mmol). After 16 hours,the reaction was quenched with 1 mL of aqueous 1N citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 10 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes to yieldcrude product. The crude material was triturated with methanol (1 mL)and filtered to provide the title compound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 11.47 (s, 1H), 8.84 (d, J=8.8 Hz, 1H), 8.20 (d,J=7.5 Hz, 2H), 7.85 (t, J=7.9 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.16-6.98(m, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 3.64 (q, J=6.9Hz, 2H), 2.70 (s, 3H), 2.22 (s, 3H), 1.21 (q, J=4.2 Hz, 2H), 0.90 (bs,2H), 0.79 (t, J=6.9 Hz, 3H). MS (APCI+) m/z 425 (M+H)⁺.

Example I-841-(5-ethyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-84A 2-bromo-4-ethyl-1-methoxybenzene

To a solution of 1-ethyl-4-methoxybenzene (2 mL, 14.10 mmol) inacetonitrile (30 mL) was added 1-bromopyrrolidine-2,5-dione (2.76 g,15.51 mmol) and the reaction was stirred under nitrogen at ambienttemperature for 16 hours. The solvent was removed in vacuo and the crudematerial taken up in water (50 mL) and hexanes (100 mL). The organicswere separated and dried over anhydrous magnesium sulfate to provide thetitle compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.39 (d, J=2.3 Hz,1H), 7.10 (dd, J=8.4, 2.2 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 3.88 (s, 3H),2.59 (q, J=7.6 Hz, 2H), 1.22 (t, J=7.6 Hz, 3H).

Example I-84B 1-(5-ethyl-2-methoxyphenyl)cyclopropanecarbonitrile

To a 100 mL round bottomed flask under nitrogen was added BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 0.463 g, 0.744 mmol) andPd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium(0), 0.341 g, 0.372mmol) and degassed tetrahydrofuran (7.59 mL) and the mixture wasdegassed and was stirred under nitrogen for 30 minutes. Then a degassedsolution of 2-bromo-4-ethyl-1-methoxybenzene (1.497 mL, 9.30 mmol) fromExample I-84A and cyclopropanecarbonitrile (1.345 mL, 13.95 mmol) incyclopentyl methyl ether (18.98 mL) was added to the catalystsuspension. To the mixture was added 1 M LiHMDS (lithiumbis(trimethylsilyl)amide, 27.9 mL, 27.9 mmol) in tetraydrofuran slowlywithin 30 minutes at ambient temperature. The reaction was heated at 80°C. overnight. The reaction was cooled to ambient temperature and dilutedwith ethyl acetate (200 mL) and saturated aqueous ammonium chloride (500mL). The organic layer was separated and the aqueous layer was backextracted twice with 100 mL of ethyl acetate. The combined organiclayers were dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified using an 80 g silica gelcartridge with a gradient of 5-100% ethyl acetate/hexanes over 40minutes to provide the title compound. ¹H NMR (400 MHz, chloroform-d) δppm 7.14 (ddd, J=8.4, 2.3, 0.8 Hz, 1H), 7.05 (d, J=2.2 Hz, 1H), 6.83 (d,J=8.4 Hz, 1H), 3.92 (d, J=0.8 Hz, 3H), 2.58 (q, J=7.6 Hz, 2H), 1.63-1.59(m, 2H), 1.30-1.24 (m, 2H), 1.21 (td, J=7.6, 0.8 Hz, 3H).

Example I-84C 1-(5-ethyl-2-methoxyphenyl)cyclopropanecarboxylic Acid

1-(5-Ethyl-2-methoxyphenyl)cyclopropanecarbonitrile (0.681 g, 3.38 mmol)from Example I-84B was dissolved in ethanol (5 mL). A solution of sodiumhydroxide (1.320 g, 33.0 mmol) in water (2.500 mL) was added, and theresulting mixture was heated at 90° C. for 16 hours. The solvent wasreduced in volume and the residue was cooled in an ice bath andacidified with 6M aqueous HCl (6 mL). The resulting precipitate wasfiltered and washed with water. The crude material was resubjected tothe reaction conditions overnight to provide the title compound. ¹H NMR(501 MHz, dimethyl sulfoxide-d₆) 6 ppm 7.01 (dd, J=8.3, 2.3 Hz, 1H),6.96 (d, J=2.3 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 3.70 (s, 3H), 2.54-2.49(m, 2H), 1.33 (q, J=3.8 Hz, 2H), 1.12 (t, J=7.5 Hz, 3H), 0.91 (q, J=3.8Hz, 2H). MS (APCI+) m/z 221 (M+H)⁺.

Example I-84D1-(5-ethyl-2-methoxyphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of 1-(5-ethyl-2-methoxyphenyl)cyclopropanecarboxylic acid(55 mg, 0.250 mmol) from Example I-84C,Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (96 mg, 0.499 mmol) and N,N-dimethylpyridin-4-amine (30.5mg, 0.250 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added2-methylquinoline-5-sulfonamide (60 mg, 0.270 mmol). The solution wasstirred at ambient temperature overnight. The reaction was quenched with1.0 mL of aqueous 1N HCl and the reaction was filtered through a syringefilter and diluted with dimethyl sulfoxide and purified by reverse-phasepreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column(30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to providethe title compound as a trifluoroacetic acid salt. ¹H NMR (400 MHz,chloroform-d) δ ppm 9.15 (d, J=8.9 Hz, 1H), 8.62 (dt, J=8.6, 1.0 Hz,1H), 8.49 (dd, J=7.6, 1.2 Hz, 1H), 8.27 (s, 1H), 7.95 (dd, J=8.5, 7.6Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.22 (dd, J=8.4, 2.3 Hz, 1H), 7.03 (d,J=2.3 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 3.68 (s, 3H), 2.96 (s, 3H), 2.62(q, J=7.6 Hz, 2H), 1.49 (q, J=4.1 Hz, 2H), 1.24 (t, J=7.6 Hz, 3H), 1.05(q, J=4.2 Hz, 2H). MS (APCI+) m/z 425 (M+H)⁺.

Example I-851-{2-methoxy-5-[1-(methylamino)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-85A 1-(3-bromo-4-methoxyphenyl)cyclopropanecarboxylic Acid

Methyl 1-(3-bromo-4-methoxyphenyl)cyclopropanecarboxylate (0.5 g, 1.754mmol, Example I-1-73B) was dissolved in tetrahydrofuran (3 mL), methanol(3 mL), and water (3 mL) and was treated with sodium hydroxide (0.351 g,8.77 mmol). The reaction mixture was stirred at 35° C. overnight,concentrated in vacuo, and quenched with 1N aqueous citric acid (about10 mL) until the pH ˜5. The resulting slurry was stirred vigorously andfiltered. The precipitate was washed with water and hexanes, and driedin a vacuum oven overnight to provide the title compound. ¹H NMR (400MHz, chloroform-d) δ ppm 7.53 (d, J=2.2 Hz, 1H), 7.25 (dd, J=2.2 Hz, 8.5Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 1.65 (q, J=4.0 Hz, 2H),1.23 (q, J=4.0 Hz, 2H). MS (ESI+) m/z 271 (M+H)⁺.

Example I-85B Tert-Butyl(1-(3-bromo-4-methoxyphenyl)cyclopropyl)carbamate

To a solution of 1-(3-bromo-4-methoxyphenyl)cyclopropanecarboxylic acid(100 mg, 0.369 mmol) from Example I-85A, 2-methylpropan-2-ol (0.141 mL,1.475 mmol) in toluene (1 mL) at ambient temperature under nitrogen in adried 20 mL vial, was added triethylamine (0.072 mL, 0.516 mmol)followed by 4 Å molecular sieves (0.13 g). The mixture was stirred for 5minutes, and diphenyl phosphorazidate (0.087 mL, 0.406 mmol) was added.The mixture was stirred another 15 minutes at ambient temperature, andfor 2 hours at 77° C. The mixture was filtered and the filtrate wasconcentrated in vacuo. The crude material was purified on a 12 gcartridge with 0-100% ethyl acetate/heptanes in 12 minutes to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.43 (d, J=2.3Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 5.21 (bs, 1H),3.87 (s, 3H), 1.43 (s, 9H), 1.22 (bs, 2H), 1.14 (bs, 2H). MS (APCI+) m/z243 (M+H-Boc)⁺.

Example I-85C Tert-Butyl(1-(3-bromo-4-methoxyphenyl)cyclopropyl)(methyl)carbamate

A suspension of NaH (25.9 mg, 0.649 mmol) in N,N-dimethylformamide (1.5mL) was cooled down to 0° C. tert-Butyl(1-(3-bromo-4-methoxyphenyl)cyclopropyl)carbamate from Example I-85B(148 mg, 0.432 mmol) was added. The mixture was stirred at 0° C. for 10minutes, warmed up to ambient temperature and stirred for 20 minutes.Iodomethane (0.035 mL, 0.562 mmol) was added neat dropwise. The mixturewas stirred at ambient temperature for 2 hours, quenched with 1 Naqueous ammonium chloride and extracted with ethyl acetate. The organiclayer was separated, dried over Na₂SO₄, filtered, and concentrated todryness. The crude material was purified on a 10 g silica gel cartridgewith a gradient of 0-100% ethyl acetate/heptanes in 12 minutes toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.38(d, J=2.3 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.6 Hz, 1H), 3.89(s, 3H), 2.91 (s, 3H), 1.47 (s, 9H), 1.29 (s, 2H), 1.17 (s, 2H). MS(ESI+) m/z=256 (M+H-Boc)⁺.

Example I-85D Tert-Butyl(1-(3-(1-cyanocyclopropyl)-4-methoxyphenyl)cyclopropyl)(methyl)carbamate

To a 100 mL round bottomed flask under nitrogen was added BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 19.58 mg, 0.031 mmol) andPd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium(0), 14.39 mg, 0.016mmol) and degassed tetrahydrofuran (321 μl). The mixture was degassedand was stirred under nitrogen for 30 minutes. A degassed solution oftert-butyl (1-(3-bromo-4-methoxyphenyl)cyclopropyl)(methyl)carbamate(140 mg, 0.393 mmol) from Example I-85C and cyclopropanecarbonitrile(56.8 μl, 0.589 mmol) in cyclopentyl methyl ether (802 μl) was added tothe catalyst suspension. To the mixture was then added 1M LiHMDS(lithium bis(trimethylsilyl)amide, 1179 μl, 1.179 mmol) intetrahydrofuran slowly within 20 minutes at ambient temperature. Thereaction was heated at 80° C. for 16 hours. The reaction was cooled toambient temperature and diluted with ethyl acetate (7 mL) and saturatedaqueous ammonium chloride (16 mL). The organic layer was separated andthe aqueous layer was back extracted twice with 10 mL of ethyl acetate.The combined organic layers were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified using a 12g silica gel cartridge with a gradient of 0-50% ethyl acetate/hexanesover 12 minutes to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.12 (dd, J=8.6, 2.3 Hz, 1H), 7.06 (bs, 1H), 6.81(d, J=8.5 Hz, 1H), 3.91 (s, 3H), 2.89 (s, 3H), 1.60 (bs, 2H), 1.46 (s,9H), 1.26 (bs, 2H), 1.25-1.19 (m, 2H), 1.14 (bs, 2H). MS (ESI+) m/z 243(M+H-Boc)⁺.

Example I-85E1-(5-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)-2-methoxyphenyl)cyclopropanecarboxylicAcid

tert-Butyl(1-(3-(1-cyanocyclopropyl)-4-methoxyphenyl)cyclopropyl)(methyl)carbamate(75 mg, 0.219 mmol) from Example I-85D was dissolved in ethanol (0.5mL). A solution of sodium hydroxide (85 mg, 2.135 mmol) in water (0.250mL) was added, and the resulting mixture was heated at 90° C. for 5days. The solvent was reduced in volume and the residue was acidifiedwith 1 M aqueous citric acid (2 mL). The resulting precipitate wasextracted with dichloromethane. The organics were concentrated andpurified on a 12 g silica gel cartridge with a gradient of 20-100% ethylacetate/heptanes over a period of 10 minutes to provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.11-7.06 (m, 1H),7.06-7.02 (bs, 1H), 6.78 (d, J=8.4 Hz, 1H), 3.81 (s, 3H), 2.88 (s, 3H),1.63 (s, 2H), 1.44 (s, 9H), 1.25 (m, 2H), 1.13 (bs, 4H). MS (APCI+) m/z262 (M+H-Boc)⁺.

Example I-85F1-{2-methoxy-5-[1-(methylamino)cyclopropyl]phenyl}-N-(quinoline-5-sulfonyl)cycpropane-1-carboxamide

To a solution of1-(5-(1-((tert-butoxycarbonyl)(methyl)amino)cyclopropyl)-2-methoxyphenyl)cyclopropanecarboxylicacid (31 mg, 0.086 mmol) from Example I-85E,Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (32.9 mg, 0.172 mmol) and N,N-dimethylpyridin-4-amine(11.53 mg, 0.094 mmol) in anhydrous dichloromethane (0.5 mL) was addedquinoline-5-sulfonamide (17.86 mg, 0.086 mmol). After 16 hours, thereaction was quenched with 1 mL of aqueous 1N citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 10 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes to yieldthe Boc-intermediate. The intermediate was treated with 0.2 mLdichloromethane and trifluoroacetic acid (0.4 mL, 5.19 mmol), andstirred for 1 hour at ambient temperature. The solvent was evaporated invacuo, and the residue was triturated with 4 mL diethyl ether. Theresulting precipitate was filtered to provide the title compound as thetrifluoroacetic acid salt. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm11.57 (s, 1H), 9.05 (d, J=3.0 Hz, 1H), 8.94 (d, J=8.8 Hz, 2H), 8.33 (d,J=8.4 Hz, 1H), 8.28 (d, J=7.3 Hz, 1H), 7.93 (t, J=8.0 Hz, 1H), 7.70 (dd,J=8.8, 4.2 Hz, 1H), 7.39 (dd, J=8.4, 2.3 Hz, 1H), 7.27 (d, J=2.3 Hz,1H), 6.92 (d, J=8.6 Hz, 1H), 3.39 (s, 3H), 2.44 (s, 3H), 1.37-1.26 (m,4H), 1.14 (d, J=6.4 Hz, 2H), 0.98 (s, 2H). MS (APCI+) m/z 452 (M+H)⁺.

Example I-861-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamideExample I-86A 1-cyclobutyl-3,5-dimethoxybenzene

In a 250 mL flask, 1-bromo-3,5-dimethoxybenzene (2 g, 9.21 mmol) [CAS#20469-65-2] was dissolved in tetrahydrofuran (120 mL) and treated withpalladium(II) acetate (0.207 g, 0.921 mmol) anddicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (0.378 g,0.921 mmol), followed by dropwise addition over a few minutes of 0.5 Mcyclobutylzinc(II) bromide (23.96 mL, 11.98 mmol) in tetrahydrofuran viaaddition funnel at ambient temperature. After 16 hours, the mixture waspoured into 80 mL of saturated aqueous ammonium chloride and extractedwith ethyl acetate (2×100 mL). The combined organics were dried oversodium sulfate, filtered, and concentrated to provide the titlecompound. MS (ESI+) m/z 193 (M+H)⁺.

Example I-86B 2-bromo-5-cyclobutyl-1,3-dimethoxybenzene

In a 250 mL round bottom flask, 1-cyclobutyl-3,5-dimethoxybenzene (1.7g, 8.84 mmol) from Example I-86A was dissolved in dichloromethane (25mL), and cooled to 0° C. in an ice bath. N-Bromosuccinimide (1.574 g,8.84 mmol) was added to the reaction. The reaction was stirred at 0° C.for 1 hour. The mixture was poured into 50 mL of saturated aqueoussodium bicarbonate and was extracted with dichloromethane (2×100 mL).The combined organics were dried over sodium sulfate, filtered, andconcentrated. The crude material was purified by silica gelchromatography (ethyl acetate/petroleum ether=1/10) to provide the titlecompound. ¹H NMR: (400 MHz, CDCl₃) δ ppm 6.52 (d, J=2.4 Hz, 1H), 6.36(d, J=2.4 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.81-3.72 (m 1H),2.46-2.39 (m, 2H), 2.12-1.96 (m, 3H), 1.84-1.77 (m, 1H).

Example I-86C Methyl1-(4-cyclobutyl-2,6-dimethoxyphenyl)cyclopropanecarboxylate

The title compound was prepared as described in Example I-1B,substituting 2-bromo-5-cyclobutyl-1,3-dimethoxybenzene from ExampleI-86B for 1-bromo-2-methoxybenzene. MS (ESI+) m/z 291 (M+H)⁺.

Example I-86D 1-(4-cyclobutyl-2,6-dimethoxyphenyl)cyclopropanecarboxylicAcid

In a 250 mL round bottom flask, methyl1-(4-cyclobutyl-2,6-dimethoxyphenyl)cyclopropanecarboxylate (3.8 g,13.09 mmol) from Example I-86C was dissolved in methanol (20 mL) andtetrahydrofuran (40 mL), and 10 M aqueous sodium hydroxide (42.3 mL, 423mmol) was added. The reaction mixture was stirred at 70° C. for 32hours, cooled in an ice bath and acidified with 6 N aqueous hydrogenchloride to pH=2. The reaction mixture was extracted with ethyl acetate(2×100 mL) and the organic extracts were washed with brine (100 mL),dried over sodium sulfate, filtered, and concentrated. The residue wastriturated with tert-butyl methyl ether (20 mL). The material wasfiltered and dried to provide the title compound. ¹HNMR: (400 MHz,CDCl₃) δ ppm 6.52 (d, J=2.0 Hz, 1H), 6.32 (d, J=2.0 Hz, 1H), 3.90-3.83(m, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 2.35-2.22 (m 2H), 2.22-2.08 (m,2H), 2.04-1.95 (m, 1H), 1.86-1.70 (m, 3H), 1.17-1.08 (m, 2H). MS (ESI+)m/z 277 (M+H)⁺.

Example I-86E

To a solution of1-(4-cyclobutyl-2,6-dimethoxyphenyl)cyclopropanecarboxylic acid (87 mg,0.315 mmol) from Example I-86D,N^(t)-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (121 mg, 0.630 mmol) and N,N-dimethylpyridin-4-amine (38.5mg, 0.315 mmol) in anhydrous dichloromethane (1 mL) was added1H-indole-4-sulfonamide (61.8 mg, 0.315 mmol). The solution was stirredat ambient temperature overnight. The reaction was quenched with 0.5 mLof aqueous 1N HCl and the crude organics were purified by reverse-phasepreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column(30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). The materialwas washed with ethyl acetate, ether and methanol to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.59 (s, 1H),10.40 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.60-7.50 (m, 2H), 7.17 (t, J=7.8Hz, 1H), 6.82-6.71 (m, 1H), 6.43-6.31 (m, 2H), 3.73 (s, 3H), 3.65 (s,3H), 3.49-3.38 (m, 1H), 2.19-2.05 (m, 1H), 2.03-1.90 (m, 1H), 1.79-1.60(m, 3H), 1.58-1.49 (m, 2H), 1.36-1.25 (m, 1H), 0.91-0.76 (m, 2H). MS(ESI+) m/z 455 (M+H)⁺.

Example I-87N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamideExample I-87A 2-bromo-1-isopropoxy-4-methylbenzene

To 2-bromo-4-methylphenol (2 g, 10.69 mmol) in N,N-dimethylformamide (10mL) was added potassium carbonate (2.96 g, 21.39 mmol) at ambienttemperature. The mixture was stirred for 10 minutes and then2-iodopropane (2.135 mL, 21.39 mmol) was added dropwise, and the mixturewas heated to 50° C. for 16 hours with stirring. Ethyl acetate (20 mL)was added, the reaction was filtered, and the material was rinsed withethyl acetate (2×20 mL). The combined organics were washed with waterand brine, dried over MgSO₄, filtered, and concentrated. The residue waspurified via chromatography on a 24 g silica gel cartridge, eluting withethyl acetate in heptane at 0-40% gradient to provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.35 (dd, J=2.1, 0.8 Hz,1H), 7.01 (ddd, J=8.3, 2.1, 0.8 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 4.47(hept, J=6.1 Hz, 1H), 2.26 (s, 3H), 1.35 (d, J=6.1 Hz, 6H). MS (APCI+)m/z 229 (M+H)⁺.

Example I-87B Methyl1-(2-isopropoxy-5-methylphenyl)cyclopropanecarboxylate

To 2-Bromo-1-isopropoxy-4-methylbenzene (2.10 g, 9.17 mmol) from ExampleI-87A in 10 mL of dry tetrahydrofuran was added Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.130 g,0.183 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.168 g, 0.183mmol). A solution of freshly-prepared(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (45.8 mL, 18.33 mmol)in tetrahydrofuran (0.40 mmol/mL, 46 mL) was added via a stainless steelcannula under nitrogen pressure. The mixture was stirred at ambienttemperature for 20 minutes. Ethyl acetate and saturated aqueous ammoniumchloride were added. The organic layer was washed with brine and wasconcentrated. The residue was purified via chromatography on a 40 gsilica gel cartridge, eluting with ethyl acetate in heptane at 0-50%gradient to provide the title compound. MS (APCI+) m/z 249 (M+H)⁺.

Example I-87C 1-(2-isopropoxy-5-methylphenyl)cyclopropanecarboxylic Acid

A mixture of methyl1-(2-isopropoxy-5-methylphenyl)cyclopropanecarboxylate (2.0 g, 8.05mmol) from Example I-87B and lithium hydroxide (1.929 g, 81 mmol) inmethanol (10 mL) and water (3 mL) were stirred at 40° C. for 16 hours.The solvent was reduced to half and was adjusted to pH ˜1 by adding 6Maqueous HCl. The mixture was extracted with dichloromethane (20 mL×3),washed with brine, dried over MgSO₄, filtered, and concentrated toprovide the title compound. ¹H NMR (500 MHz, chloroform-d) δ ppm7.09-6.96 (m, 2H), 6.79-6.68 (m, 1H), 4.53 (pd, J=6.1, 0.6 Hz, 1H), 2.25(t, J=0.7 Hz, 3H), 1.60 (q, J=4.1 Hz, 2H), 1.30 (d, J=6.0 Hz, 6H), 1.13(q, J=4.1 Hz, 2H). MS (APCI+) m/z 235 (M+H)⁺.

Example I-87D 2-(diallylamino)quinoline-5-sulfonamide

5-Bromo-2-chloroquinoline (8 g, 33.0 mmol) was dissolved in1-methyl-2-pyrrolidinone (33.0 mL). Diallylamine (12.22 mL, 99 mmol) wasadded, and the resulting solution was heated at 100° C. for 30 hours,adding more (3×8 mL) portions of allylamine spread over that time. Thereaction was reduced in volume, diluted with water (100 mL), andextracted with methyl tert-butyl ether (3×100 mL). The combined extractswere washed with water (50 mL) and brine (50 mL) and dried over sodiumsulfate. After filtration, the solvent was removed in vacuo and thecrude material was purified via silica gel chromatography, eluting with0-5% ethyl acetate in hexanes to giveN,N-diallyl-5-bromoquinolin-2-amine (10 g, 33.0 mmol). TheN,N-diallyl-5-bromoquinolin-2-amine was dissolved in tetrahydrofuran(165 mL) and the solution was cooled to <−70° C. before addition ofn-butyllithium (2.5M in hexane, 14.45 mL, 36.3 mmol) dropwise overapproximately 5 minutes, maintaining an internal temperature below −68°C. The resulting mixture was stirred for 2 minutes at the sametemperature and quenched by SO₂ (g) addition. The mixture wasconcentrated in vacuo to provide lithium2-(diallylamino)quinoline-5-sulfinate (9.71 g, 33.0 mmol). The lithium2-(diallylamino)quinoline-5-sulfinate was then dissolved in water (66.0mL) and sodium acetate trihydrate (6.29 g, 46.2 mmol) and(aminooxy)sulfonic acid (5.22 g, 46.2 mmol) were added in one portion.The reaction mixture was stirred at ambient temperature for 1 hour, 2 mLof tetrahydrofuran was added, and stirring was continued for another 30minutes at ambient temperature. After 90 minutes the reaction wasfiltered, and the material was washed with water and heptanes. The crudematerial was dissolved in 300 mL of ethyl acetate, washed with water andbrine, dried over sodium sulfate, filtered, and concentrated in vacuo.The crude material was purified by silica gel chromatography, elutingwith ethyl acetate in heptanes (0 to 40%) to provide the title compound.¹H NMR (400 MHz, chloroform-d) δ ppm 8.64 (dd, J=9.6, 0.8 Hz, 1H),8.00-7.85 (m, 2H), 7.53 (dd, J=8.5, 7.4 Hz, 1H), 6.95 (d, J=9.6 Hz, 1H),5.91 (ddt, J=17.2, 10.5, 5.2 Hz, 2H), 5.25-5.15 (m, 4H), 4.89 (s, 2H),4.27 (dt, J=5.5, 1.7 Hz, 4H).

Example I-87EN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(2-isopropoxy-5-methylphenyl)cyclopropanecarboxamide

To a solution of 1-(2-isopropoxy-5-methylphenyl)cyclopropanecarboxylicacid (50 mg, 0.213 mmol) from Example I-87C, N,N-dimethylpyridin-4-amine(26.1 mg, 0.213 mmol) andN-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (82 mg, 0.427 mmol) in dichloromethane (1 mL) was added2-(diallylamino)quinoline-5-sulfonamide (78 mg, 0.257 mmol) from ExampleI-87D. The reaction mixture was stirred at ambient temperature for 5hours, and quenched with 0.5 mL of 1N aqueous HCl. The organics werepurified using a 12 g silica gel cartridge with a gradient of 0-100%ethyl acetate/hexanes over 20 minutes to provide the title compound. ¹HNMR (501 MHz, chloroform-d) δ ppm 8.47-8.39 (m, 2H), 8.07 (dd, J=7.5,1.2 Hz, 1H), 7.93 (dt, J=8.4, 1.0 Hz, 1H), 7.60 (dd, J=8.5, 7.5 Hz, 1H),7.14 (ddd, J=8.4, 2.3, 0.8 Hz, 1H), 7.06-7.00 (m, 1H), 6.85 (d, J=9.6Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.00-5.89 (m, 2H), 5.24 (dq, J=7.2, 1.6Hz, 2H), 5.23-5.19 (m, 2H), 4.50 (hept, J=6.1 Hz, 1H), 4.29 (dt, J=5.5,1.6 Hz, 4H), 2.30 (s, 3H), 1.51 (t, J=3.2 Hz, 2H), 1.22 (d, J=6.0 Hz,6H), 1.00 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 520 (M+H)⁺.

Example I-87FN-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]phenyl}cyclopropane-1-carboxamide

N-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(2-isopropoxy-5-methylphenyl)cyclopropanecarboxamide(30 mg, 0.058 mmol) was dissolved in ethanol (0.5 mL) and water (0.5mL), degassed with a stream of nitrogen bubbling through, and treatedwith RhCl(PPh₃)₃ (Wilkinson's catalyst,chloridotris(triphenylphosphane)rhodium(I), 2.67 mg, 2.89 μmol). Thereaction mixture was stirred at 100° C. After 5 hours, the solvent wasreduced in volume and the reaction was filtered. The precipitate waswashed with ether to give crude material which was purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.64 (s, 1H), 8.87 (d, J=9.8 Hz, 1H), 8.61 (s, 2H), 7.99 (dd,J=7.0, 1.8 Hz, 1H), 7.92-7.75 (m, 2H), 7.11 (d, J=9.8 Hz, 1H), 7.00 (dd,J=8.4, 2.2 Hz, 1H), 6.90 (d, J=2.2 Hz, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.40(p, J=6.0 Hz, 1H), 2.19 (s, 3H), 1.22 (q, J=4.2 Hz, 2H), 1.00 (d, J=6.0Hz, 6H), 0.91 (q, J=4.3 Hz, 2H). MS (ESI+) m/z 440 (M+H)⁺.

Example I-881-[2-methoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-88A 1-(4-methoxyphenyl)cyclobutanol

(4-Methoxyphenyl)magnesium bromide (121 mL, 60.5 mmol) solution wascooled to −78° C. before dropwise addition of cyclobutanone (4.76 mL,63.7 mmol). After the addition was complete, the reaction was warmed toambient temperature and quenched with saturated aqueous ammoniumchloride. The mixture was diluted with methyl tert-butyl ether. Theorganic layer was washed with saturated aqueous ammonium chloride andbrine, dried over sodium sulfate, filtered and concentrated to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.50-7.40 (m,2H), 6.97-6.89 (m, 2H), 3.84 (s, 3H), 2.65-2.53 (m, 2H), 2.45-2.31 (m,2H), 2.17-2.07 (m, 1H), 2.07-1.94 (m, 1H), 1.74-1.60 (m, 1H).

Example I-88B 1-methoxy-4-(1-methoxycyclobutyl)benzene

To a cooled (ice bath) solution of 1-(4-methoxyphenyl)cyclobutanol (7.10g, 39.8 mmol) from Example I-88A in N,N-dimethylformamide (66.4 mL) wasadded sodium hydride (2.390 g, 59.8 mmol) and the reaction was stirredat 5° C. for one hour. Iodomethane (4.96 mL, 80 mmol) was added and thereaction was allowed to warm to ambient temperature and was stirred for16 hours. Water was added and the solution was diluted with methyltert-butyl ether (400 mL). The organic layer was separated and driedover sodium sulfate, filtered and concentrated under reduced pressure toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm7.39-7.30 (m, 2H), 6.95-6.75 (m, 2H), 3.82 (s, 3H), 2.91 (s, 3H),2.44-2.27 (m, 4H), 1.91 (dtt, J=11.1, 9.3, 4.9 Hz, 1H), 1.64 (dp,J=11.0, 8.5 Hz, 1H).

Example I-88C 2-bromo-1-methoxy-4-(1-methoxycyclobutyl)benzene

A solution of 1-methoxy-4-(1-methoxycyclobutyl)benzene (8 g, 41.6 mmol)from Example I-88B and N-bromosuccinimide (8.15 g, 45.8 mmol) inacetonitrile (41.6 mL) was stirred at ambient temperature for 3 hours.The solvent was evaporated in vacuo. The crude material was trituratedwith dichloromethane, and filtered. The filtrate was purified bychromatography, eluting on 40 g silica gel cartridge with a gradient of0-20% ethyl acetate/heptanes over a period of 12 minutes to provide thetitle compound. H NMR (501 MHz, chloroform-d) δ ppm 7.60 (d, J=2.2 Hz,1H), 7.33 (dd, J=8.5, 2.2 Hz, 1H), 6.90 (d, J=8.5 Hz, 1H), 3.91 (s, 3H),2.92 (s, 3H), 2.35 (d, J=7.1 Hz, 2H), 2.34 (d, J=7.0 Hz, 2H), 2.01-1.87(m, 1H), 1.65 (dq, J=11.2, 8.4 Hz, 1H). MS (APCI+) m/z 239(M+H-methanol)⁺.

Example I-88D Methyl1-(2-methoxy-5-(1-methoxycyclobutyl)phenyl)cyclopropanecarboxylate

To a solution of Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene, 0.052 g,0.074 mmol) and bis(dibenzylideneacetone)palladium (0.042 g, 0.074 mmol)in tetrahydrofuran (12 mL) at ambient temperature was added2-bromo-1-methoxy-4-(1-methoxycyclobutyl)benzene (1 g, 3.69 mmol) fromExample I-88C followed by a solution of freshly-prepared(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (16.39 mL, 7.38 mmol).The mixture was stirred at ambient temperature for 16 hours.Dichloromethane and saturated aqueous ammonium chloride were added. Theorganic layer was separated, washed with brine and concentrated. Theresidue was purified via chromatography on a 40 g silica gel cartridge,eluting with ethyl acetate in heptane at 0-50% gradient in a period of15 minutes to provide the title compound. ¹H NMR (501 MHz, chloroform-d)δ ppm 7.30 (dd, J=8.4, 2.4 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 6.85 (d,J=8.4 Hz, 1H), 3.84 (s, 3H), 3.60 (s, 3H), 2.91 (s, 3H), 2.42-2.28 (m,4H), 1.92 (dtt, J=11.1, 9.3, 4.9 Hz, 1H), 1.66 (dq, J=11.1, 8.4 Hz, 1H),1.60 (q, J=4.1 Hz, 2H), 1.12 (q, J=4.1 Hz, 2H). MS (APCI+) m/z 259(M+H-methanol)⁺.

Example I-88E1-(2-methoxy-5-(1-methoxycyclobutyl)phenyl)cyclopropanecarboxylic Acid

Methyl1-(2-methoxy-5-(1-methoxycyclobutyl)phenyl)cyclopropanecarboxylate (0.29g, 0.999 mmol) from Example I-88D was dissolved in tetrahydrofuran (1.5mL) and methanol (1.500 mL), and water (1.500 mL) and treated withsodium hydroxide (0.200 g, 4.99 mmol). The reaction mixture was stirredat 35° C. overnight, and the reaction was concentrated, cooled in an icebath and carefully quenched with 1N citric acid (about 2.5 mL) until thepH ˜5. The resulting slurry was stirred vigorously and filtered. Theprecipitate was washed with water and dried in a vacuum oven overnightto provide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.30(dd, J=8.4, 2.3 Hz, 1H), 7.25 (d, J=2.3 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H),3.85 (s, 3H), 2.89 (s, 3H), 2.41-2.28 (m, 4H), 1.91 (dtd, J=11.2, 9.2,4.6 Hz, 1H), 1.70-1.57 (m, 3H), 1.18 (q, J=4.1 Hz, 2H). MS (APCI+) m/z245 (M+H-methanol)⁺.

Example I-88F1-[2-methoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-methoxy-5-(1-methoxycyclobutyl)phenyl)cyclopropanecarboxylic acid(60 mg, 0.217 mmol) from Example I-88E,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (83 mg, 0.434 mmol) and N,N-dimethylpyridin-4-amine (29.2mg, 0.239 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (45.2 mg, 0.217 mmol). After 16 hours, thereaction was quenched with 1 mL of aqueous 1N citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 10 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. Thematerial was triturated with diethyl ether (3 mL) and filtered toprovide the title compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δppm 11.58 (s, 1H), 9.06 (dd, J=4.2, 1.5 Hz, 1H), 8.97 (d, J=8.7 Hz, 1H),8.34 (d, J=8.6 Hz, 1H), 8.31 (d, J=7.4 Hz, 1H), 7.94 (t, J=7.9 Hz, 1H),7.70 (dd, J=8.8, 4.1 Hz, 1H), 7.28 (dd, J=8.5, 2.3 Hz, 1H), 7.07 (d,J=2.3 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 3.38 (s, 3H), 2.82 (s, 3H), 2.32(ddd, J=12.9, 8.6, 4.7 Hz, 2H), 2.24 (ddd, J=12.2, 9.5, 7.9 Hz, 2H),1.84 (ddq, J=10.9, 9.3, 4.8 Hz, 1H), 1.58 (dp, J=10.9, 8.4 Hz, 1H), 1.31(q, J=4.3 Hz, 2H), 0.95 (s, 2H). MS (APCI+) m/z 467 (M+H)⁺.

Example I-89N-(2-aminoquinoline-5-sulfonyl)-1-(2-ethoxy-5-methylphenyl)cyclopropane1-carboxamide Example I-89A1-(2-ethoxy-5-methylphenyl)cyclopropanecarbonitrile

To a 250 mL round bottomed flask under nitrogen was added BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1.033 g, 1.658 mmol) andPd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium(0), 0.759 g, 0.829mmol) and degassed tetrahydrofuran (16.92 mL). The mixture was degassedand was stirred under nitrogen for 30 minutes. A degassed solution of2-bromo-1-ethoxy-4-methylbenzene (4.459 g, 20.73 mmol) [CAS#103260-55-5] and cyclopropanecarbonitrile (3.00 mL, 31.1 mmol) incyclopentyl methyl ether (42.3 mL) was added to the catalyst suspension.To this mixture was added 1 M lithium bis(trimethylsilyl)amide (62.2 mL,62.2 mmol) in tetrahydrofuran slowly within 30 minutes at ambienttemperature. The reaction was heated at 80° C. overnight. The reactionwas cooled to ambient temperature and was diluted with methyl tert-butylether (200 mL) and saturated aqueous ammonium chloride (140 mL). Theorganic layer was separated and the aqueous layer was back extractedtwice with 250 mL of methyl tert-butyl ether. The combined organiclayers were dried over sodium sulfate, filtered through a plug of silicagel and concentrated under reduced pressure. The residue was purifiedusing a 120 g silica gel cartridge with a gradient of 0-100% ethylacetate/hexanes over 60 minutes to provide the title compound. ¹H NMR(400 MHz, chloroform-d) δ ppm 7.08 (dd, J=8.3, 2.2 Hz, 1H), 7.02 (d,J=2.3 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 4.12 (q, J=6.9 Hz, 2H), 2.27 (s,3H), 1.63-1.57 (m, 2H), 1.50 (t, J=6.9 Hz, 3H), 1.30-1.22 (m, 2H). MS(ESI+) m/z 202 (M+H)⁺.

Example I-89B 1-(2-ethoxy-5-methylphenyl)cyclopropanecarboxylic Acid

1-(2-Ethoxy-5-methylphenyl)cyclopropanecarbonitrile (2.865 g, 14.24mmol) from Example I-89A was dissolved in ethanol (10 mL). A solution ofsodium hydroxide (5.392 g, 135 mmol) in water (5.00 mL) was added, andthe resulting mixture was heated at 90° C. After 1 hour, additionalethanol (10 mL) was added and the reaction continued heating at 90° C.for 72 hours. The reaction was poured into an ice cooled solution of 6 Naqueous hydrogen chloride (23.13 mL, 139 mmol) to acidic pH. Theresulting precipitate was filtered and washed with water to provide thetitle compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.85 (s,1H), 6.98-6.90 (m, 2H), 6.78 (d, J=8.1 Hz, 1H), 3.95 (q, J=7.0 Hz, 2H),2.17 (s, 3H), 1.34 (q, J=3.9 Hz, 2H), 1.23 (t, J=6.9 Hz, 3H), 0.95 (q,J=3.9 Hz, 2H). MS (ESI−) m/z 218 (M−H)⁻.

Example I-89CN-(2-aminoquinoline-5-sulfonyl)-1-(2-ethoxy-5-methylphenyl)cyclopropane-1-carboxamide

To a solution of 1-(2-ethoxy-5-methylphenyl)cyclopropanecarboxylic acid(0.1 g, 0.454 mmol) from Example I-89B,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (0.174 g, 0.908 mmol) and N,N-dimethylpyridin-4-amine(0.061 g, 0.499 mmol) in anhydrous dichloromethane (2 mL) was added2-(diallylamino)quinoline-5-sulfonamide (0.138 g, 0.454 mmol) fromExample I-87D. After 1 hour, the reaction was quenched with 1 mL ofaqueous 1N HCl and put through an aqueous/organic extractor tube withdichloromethane. The solvent was removed to give crudeN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(2-ethoxy-5-methylphenyl)cyclopropanecarboxamide.The crudeN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(2-ethoxy-5-methylphenyl)cyclopropanecarboxamidewas deprotected by diluting with 0.5 mL of ethanol and 0.5 mL of water,degassing with nitrogen, and adding RhCl(PPh₃)₃ (Wilkinson's catalyst,chloridotris(triphenylphosphane)rhodium(I), 3.4 mg, 3.67 μmol). Thereaction was heated at 100° C. for 3 hours. Additional RhCl(PPh₃)₃(10mg) was added and the mixture was stirred at 100° C. for another 3hours. The mixture was concentrated and the residue was purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A).The material was triturated with methanol to provide the title compoundas the trifluoroacetic acid salt. ¹H NMR (501 MHz, dimethylsulfoxide-d₆) 6 ppm 8.83 (d, J=9.7 Hz, 1H), 8.58 (s, 2H), 8.00 (dd,J=7.2, 1.6 Hz, 1H), 7.91-7.81 (m, 2H), 7.11 (d, J=9.7 Hz, 1H), 7.04 (dd,J=8.3, 2.1 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.76 (d, J=8.2 Hz, 1H), 3.77(q, J=6.9 Hz, 2H), 2.21 (s, 3H), 1.22 (q, J=4.2 Hz, 2H), 0.97 (t, J=6.9Hz, 3H), 0.93 (q, J=4.3 Hz, 2H). MS (ESI−) m/z 424 (M−H)⁻.

Example I-901-[2-methoxy-5-(oxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-90A 3-(4-methoxyphenyl)oxetan-3-ol

To a cooled (ice/brine bath) solution of 0.5 M(4-methoxyphenyl)magnesium bromide (102 mL, 51.0 mmol) intetrahydrofuran (5 mL) was added oxetan-3-one (3.061 g, 42.5 mmol)dropwise, keeping the internal temperature below 0° C. The reaction wasallowed to slowly warm to ambient temperature and was stirred for 16hours. The reaction was cooled in an ice bath, quenched with saturatedaqueous ammonium chloride (100 mL) and diluted with methyl tert-butylether (500 mL). The organic layer was separated, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The materialwas triturated with diethyl ether. The residue was purified using an 80g silica gel cartridge with a gradient of 5-50% ethyl acetate/hexanesover 40 minutes to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.51-7.46 (m, 2H), 6.97-6.92 (m, 2H), 4.92-4.85 (m,4H), 3.83 (s, 3H), 3.14 (s, 1H). MS (ESI+) m/z 378 (2M+NH₄)⁺, 383(2M+Na)⁺.

Example I-90B 3-(4-methoxyphenyl)oxetane

To a cooled (ice bath) solution of 3-(4-methoxyphenyl)oxetan-3-ol (1.679g, 9.32 mmol) from Example I-90A and triethylsilane (1.651 mL, 10.34mmol) in dichloromethane (24 mL) was added 2,2,2-trifluoroacetic acid(7.90 mL, 102 mmol) and the reaction was allowed to warm to ambienttemperature. After about 4 hours, the reaction was quenched by slowlypouring it into a rapidly stirring solution of saturated aqueous sodiumbicarbonate (100 mL) and when the bubbling had subsided (pH mildlybasic) the solution was diluted with methyl tert-butyl ether (500 mL).The organic layer was separated and dried over sodium sulfate, filteredand concentrated under reduced pressure to provide the title compound.¹H NMR (400 MHz, chloroform-d) δ ppm 7.38-7.31 (m, 2H), 6.96-6.89 (m,2H), 5.06 (dd, J=8.4, 6.0 Hz, 2H), 4.76 (dd, J=6.9, 6.0 Hz, 2H), 4.20(tt, J=8.4, 6.9 Hz, 1H), 3.83 (s, 3H). MS (ESI+) m/z 189 (M+H)⁺.

Example I-90C 3-(3-bromo-4-methoxyphenyl)oxetane

To a solution of 3-(4-methoxyphenyl)oxetane (1.45 g, 8.83 mmol) fromExample I-90B in acetonitrile (25 mL) was added1-bromopyrrolidine-2,5-dione (1.729 g, 9.71 mmol) and the reaction wasstirred under nitrogen at ambient temperature for 15 hours. Additional1-bromopyrrolidine-2,5-dione (0.891 g) was added and stirring wascontinued for 30 minutes. The solvent was removed in vacuo and the crudematerial taken up in water (50 mL) and hexanes (100 mL). The organicswere removed, dried over anhydrous sodium sulfate, filtered, andconcentrated. The crude material was purified using an 80 g silica gelcartridge with a gradient of 0-50% ethyl acetate/hexanes over 40 minutesto provide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.60(d, J=2.2 Hz, 1H), 7.33-7.30 (m, 1H), 6.91 (d, J=8.4 Hz, 1H), 5.06 (dd,J=8.3, 6.1 Hz, 2H), 4.72 (dd, J=6.7, 6.1 Hz, 2H), 4.16 (tt, J=8.4, 6.7Hz, 1H), 3.91 (s, 3H).

Example I-90D Methyl1-(2-methoxy-5-(oxetan-3-yl)phenyl)cyclopropanecarboxylate

To a solution of 3-(3-bromo-4-methoxyphenyl)oxetane (1.100, 4.52 mmol)from Example I-90C in tetrahydrofuran (5 mL) was addedbis(dibenzylideneacetone)palladium (0.052 g, 0.090 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.064 g,0.090 mmol). Nitrogen was bubbled through the solution for about 3minutes, and a 0.4 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (20.11 mL, 9.05 mmol)was added dropwise over 5 minutes. The reaction mixture was stirred for15 hours at ambient temperature, at which point it was quenched withsaturated aqueous ammonium chloride (50 mL), diluted with methyltert-butyl ether (400 mL), and the layers were separated. The organiclayer was filtered and concentrated in vacuo. The residue was purifiedon a 80 g silica gel cartridge with 0-50% ethyl acetate/hexanes over 40minutes to provide the title compound. ¹H NMR (400 MHz, chloroform-d) δppm 7.37-7.31 (m, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H),5.05 (dd, J=8.4, 6.0 Hz, 2H), 4.76 (dd, J=6.9, 6.0 Hz, 2H), 4.18 (tt,J=8.4, 6.9 Hz, 1H), 3.85 (s, 3H), 3.62 (s, 3H), 1.63 (q, J=4.1 Hz, 2H),1.13 (q, J=4.1 Hz, 2H). MS (APCI+) m/z 263 (M+H)⁺.

Example I-90E 1-(2-methoxy-5-(oxetan-3-yl)phenyl)cyclopropanecarboxylicAcid

Methyl 1-(2-methoxy-5-(oxetan-3-yl)phenyl)cyclopropanecarboxylate (1.141g, 4.35 mmol) from Example I-90D was dissolved in tetrahydrofuran (3.0mL), methanol (3.0 mL) and water (3.0 mL), treated with sodium hydroxide(1.218 g, 30.4 mmol), and stirred at 70° C. for 3 hours. The reactionwas reduced in volume, cooled in an ice bath and carefully quenched withconcentrated aqueous HCl (about 2.5 mL) until the pH was acidic. Theresulting slurry was stirred vigorously, and filtered. The precipitatewas washed with water and dried in a vacuum oven overnight to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.33 (dd,J=8.4, 2.4 Hz, 1H), 7.23 (d, J=2.3 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 5.04(dd, J=8.4, 6.0 Hz, 2H), 4.75 (dd, J=6.9, 6.0 Hz, 2H), 4.21-4.12 (m,1H), 3.85 (s, 3H), 1.68 (q, J=4.1 Hz, 2H), 1.19 (q, J=4.1 Hz, 2H). MS(ESI−) m/z 247 (M−H)⁻.

Example I-90F1-[2-methoxy-5-(oxetan-3-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-methoxy-5-(oxetan-3-yl)phenyl)cyclopropanecarboxylic acid (53 mg,0.213 mmol) from Example I-90E,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (82 mg, 0.427 mmol) and N,N-dimethylpyridin-4-amine (28.7mg, 0.235 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (50 mg, 0.240 mmol). The reaction was stirred atambient temperature for 16 hours. The reaction was quenched with 0.5 mLof 1N aqueous HCl and the reaction was put through an aqueous/organicextractor tube with dichloromethane. The organic layer was concentratedand purified by reverse-phase preparative HPLC on a Phenomenex® Luna®C8(2) 5 μm 100 Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rateof 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient95-10% A) to provide the title compound as a trifluoroacetic acid salt.¹H NMR (400 MHz, chloroform-d) δ ppm 9.23-9.08 (m, 2H), 8.66-8.44 (m,2H), 8.40-8.06 (m, 1H), 7.98 (t, J=8.0 Hz, 1H), 7.72 (dd, J=8.8, 4.5 Hz,1H), 7.47 (dd, J=8.5, 2.3 Hz, 1H), 7.23 (d, J=2.3 Hz, 1H), 6.94 (d,J=8.5 Hz, 1H), 5.11 (dd, J=8.3, 6.1 Hz, 2H), 4.96-4.88 (m, OH), 4.73 (t,J=6.4 Hz, 2H), 4.67-4.61 (m, OH), 4.24-4.12 (m, 1H), 4.08 (t, J=10.4 Hz,OH), 3.65 (s, 3H), 1.51 (q, J=4.2 Hz, 2H), 1.04 (q, J=4.3 Hz, 2H). MS(ESI−) m/z 437 (M−H)⁻.

Example I-911-(2-ethoxy-5-methylphenyl)-N-(2-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamideExample I-91A 1-(2-bromophenyl)propan-2-one Oxime

A solution of 2-bromophenylacetone (5.00 g, 23.47 mmol), hydroxylaminehydrochloride (1.680 g, 24.17 mmol) and sodium acetate (1.981 g, 24.15mmol) in methanol (160 mL) and water (8 mL) was stirred at ambienttemperature for 15 hours. The solvent was removed in vacuo and the crudematerial was added to 500 mL of methyl tert-butyl ether and washed with50 mL each of water, saturated aqueous sodium bicarbonate, and brine.The organics were dried over sodium sulfate, filtered, and concentratedto provide the title compound. MS (ESI+) m/z 228, 230 Br doublet (M+H)⁺.

Example I-91B 2-(2-bromophenyl)-3-methyl-2H-azirine

To a solution of 1-(2-bromophenyl)propan-2-one oxime (5.17 g, 22.67mmol) from Example I-91A and N-ethyl-N-isopropylpropan-2-amine (7.92 mL,45.3 mmol) in anhydrous tetrahydrofuran (227 mL) at ambient temperaturewas added dropwise a solution of methanesulfonyl chloride (3.53 mL, 45.3mmol) in 20 mL of anhydrous tetrahydrofuran via cannula. After stirringat ambient temperature for 1 hour, 1,8-diazabicyclo[5.4.0]undec-7-ene(13.67 mL, 91 mmol) was added dropwise. Stirring was continued atambient temperature for 1 hour. The reaction mixture was passed througha pad of silica gel, concentrated in vacuo and purified using an 120 gsilica gel cartridge with 10% ethyl acetate/hexanes to provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.54 (dd, J=8.0, 1.2 Hz,1H), 7.23 (td, J=7.6, 1.2 Hz, 1H), 7.13-7.06 (m, 1H), 6.73 (dd, J=7.8,1.7 Hz, 1H), 3.25 (s, 1H), 2.54 (s, 3H). MS (ESI+) m/z (M+H)⁺.

Example I-91C 4-bromo-2-methyl-1H-indole

A solution of 2-(2-bromophenyl)-3-methyl-2H-azirine (1.73 g, 8.24 mmol)from Example I-91B in o-xylene (27.5 mL) was heated at 170° C.overnight. The reaction mixture was purified using an 80 g silica gelcartridge with 0-100% ethyl acetate/hexanes to provide the titlecompound. ¹H NMR (501 MHz, chloroform-d) δ ppm 8.01 (s, 1H), 7.29-7.22(m, 2H), 6.99 (t, J=7.8 Hz, 1H), 6.32 (dq, J=2.2, 1.0 Hz, 1H), 2.48 (d,J=0.9 Hz, 3H). MS (ESI−) m/z 208 (M−H)⁻.

Example I-91D 2-methyl-1H-indole-4-sulfonamide

A solution of 4-bromo-2-methyl-1H-indole (0.978 g, 4.66 mmol) fromExample I-91C, 1,4-diazabicyclo[2.2.2]octane-1,4-diium-1,4-disulfinate(0.671 g, 2.79 mmol), PdCl₂(AmPhos)₂(bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),0.165 g, 0.233 mmol) in 2-propanol (23.28 mL) andN-ethyl-N-isopropylpropan-2-amine (2.439 mL, 13.97 mmol) was spargedwith nitrogen and heated at 75° C. overnight. The reaction mixture wascooled to ambient temperature and filtered to give crude1-(tert-butoxycarbonyl)-1H-indazole-4-sulfinate. To the solution wasadded 40 mL of water, followed by sodium acetate (0.458 g, 5.59 mmol)and (aminooxy)sulfonic acid (0.632 g, 5.59 mmol). The mixture wasstirred at ambient temperature for 72 hours. Additional sodium acetate(0.458 g, 5.59 mmol) and (aminooxy)sulfonic acid (0.632 g, 5.59 mmol)were added. After 4 hours, Hunig's base (2 mL) was added to make thereaction mixture more basic, and additional (aminooxy)sulfonic acid(0.632 g, 5.59 mmol) was added. An hour later, the solvent was reducedin volume and the mixture was extracted with 2×200 mL ethyl acetate. Thecombined organics were dried over sodium sulfate, filtered, and thesolvent removed in vacuo. The crude material was purified using a 40 gsilica gel cartridge with an ethyl acetate/hexanes solvent system toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.32 (s, 1H), 7.45 (dt, J=8.1, 0.9 Hz, 1H), 7.39 (dd, J=7.5, 0.9Hz, 1H), 7.12 (s, 2H), 7.06 (t, J=7.8 Hz, 1H), 6.52 (dt, J=2.0, 1.0 Hz,1H), 2.39 (d, J=0.8 Hz, 3H). MS (ESI−) m/z 208 (M−H)⁻.

Example I-91E1-(2-ethoxy-5-methylphenyl)-N-(2-methyl-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

To a solution of 1-(2-ethoxy-5-methylphenyl)cyclopropanecarboxylic acid(60 mg, 0.272 mmol) from Example I-89B,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (104 mg, 0.545 mmol) and N,N-dimethylpyridin-4-amine (36.6mg, 0.300 mmol) in anhydrous dichloromethane (1 mL) was added2-methyl-1H-indole-4-sulfonamide (57.3 mg, 0.272 mmol) from ExampleI-91D. The reaction was stirred at ambient temperature for 15 hours andquenched with 0.5 mL of 1N aqueous HCl. The crude material was purifiedusing a 1 2 g silica gel cartridge with a gradient of 0-10%methanol/dichloromethane and the resulting product was triturated withmethanol to provide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.42 (s, 1H), 10.52 (s, 1H), 7.52 (d, J=8.0 Hz,1H), 7.48 (dd, J=7.7, 0.9 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 7.04-7.00 (m,1H), 6.92 (d, J=2.2 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 6.42 (dt, J=2.0,0.9 Hz, 1H), 3.75 (q, J=7.0 Hz, 2H), 2.39 (d, J=1.0 Hz, 3H), 2.19 (s,3H), 1.21 (q, J=4.2 Hz, 2H), 0.94 (t, J=6.9 Hz, 3H), 0.89 (q, J=4.4 Hz,2H). MS (APCI+) m/z 413 (M+H)⁺.

Example I-92N-(2-aminoquinoline-5-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide

To a solution of1-(5-isobutoxy-2-methoxy-4-pyridyl)cyclopropanecarboxylic acid (33 mg,0.124 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (47.7 mg, 0.249 mmol) and N,N-dimethylpyridin-4-amine (24mg, 0.196 mmol) in anhydrous dichloromethane (1 mL) was added2-(diallylamino)quinoline-5-sulfonamide (47 mg, 0.155 mmol) from ExampleI-87D. The reaction was stirred at ambient temperature overnight. Thereaction was quenched with 0.2 mL of aqueous 1N HCl and purified using a12 g silica gel cartridge with a gradient of 5-100% ethylacetate/hexanes over 20 minutes to provideN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(5-isobutoxy-2-methoxypyridin-4-yl)cyclopropanecarboxamide.TheN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(5-isobutoxy-2-methoxypyridin-4-yl)cyclopropanecarboxamidewas dissolved in ethanol (0.5 mL) and water (0.5 mL), degassed with astream of nitrogen bubbling through, and treated with RhCl(PPh₃)₃(Wilkinson's catalyst, chloridotris(triphenylphosphane)rhodium(I), 3.2mg, 3.46 μmol). The reaction was stirred at 100° C. After 4 hours,RhCl(PPh₃)₃(1 mg) was added and stirring was continued with heatingovernight. The reaction was cooled and the resulting precipitate wastriturated with ether. The precipitate was purified by reverse-phasepreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column(30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to providethe title compound as a trifluoroacetic acid salt. ¹H NMR (400 MHz,dimethyl sulfoxide-d₆) δ ppm 8.78 (d, J=9.8 Hz, 1H), 8.01 (dd, J=7.0,1.8 Hz, 1H), 7.94-7.82 (m, 2H), 7.65 (s, 1H), 7.14 (d, J=9.8 Hz, 1H),6.61 (s, 1H), 3.76 (s, 3H), 3.44 (d, J=6.4 Hz, 2H), 1.36 (dt, J=13.2,6.6 Hz, 1H), 1.29 (q, J=4.4 Hz, 2H), 1.02 (q, J=4.5 Hz, 2H), 0.68 (d,J=6.7 Hz, 6H). MS (ESI+) m/z 471 (M+H)⁺.

Example I-931-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-93A 3-(2-bromo-4-methylphenoxy)oxetane

To 2-bromo-4-methylphenol (1.3 mL, 10.63 mmol) in N,N-dimethylformamide(10 mL) was added potassium carbonate (2.94 g, 21.25 mmol) at ambienttemperature. The mixture was stirred at ambient temperature for 10minutes before adding 3-bromooxetane (2.91 g, 21.25 mmol) dropwise. Thereaction was heated at 50° C. for 72 hours with stirring. Ethyl acetate(100 mL) was added and the reaction was filtered. The material waswashed with ethyl acetate (50 mL) two times. The combined organics werewashed with water and brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified via chromatography on a 80 gsilica gel cartridge, eluting with ethyl acetate in heptane at 0-40%gradient to provide the title compound. ¹H NMR (400 MHz, chloroform-d) δppm 7.40 (d, J=2.1 Hz, 1H), 7.01 (dd, J=8.3, 2.1 Hz, 1H), 6.37 (d, J=8.2Hz, 1H), 5.21 (p, J=5.7 Hz, 1H), 4.97 (dd, J=7.4, 6.2 Hz, 2H), 4.87-4.81(m, 2H), 2.28 (s, 3H).

Example I-93B Methyl1-(5-methyl-2-(oxetan-3-yloxy)phenyl)cyclopropanecarboxylate

To a solution of 3-(2-bromo-4-methylphenoxy)oxetane (1.724 g, 7.09 mmol)from Example I-93A in tetrahydrofuran (6 mL) was addedbis(dibenzylideneacetone)palladium (0.082 g, 0.142 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.101 g,0.142 mmol). Nitrogen was bubbled through the solution for about 3minutes, then a 0.54M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (26.3 mL, 14.18 mmol)was added dropwise over 5 minutes. The reaction was stirred for 3 hoursat ambient temperature. The reaction was quenched with saturated aqueousammonium chloride (50 mL), diluted with methyl tert-butyl ether (400mL), and the layers were separated. The organic layer was filtered andconcentrated in vacuo. The residue was purified via flashchromatography, eluting on an 80 g silica gel cartridge with 0-50% ethylacetate/hexanes over 40 minutes to provide the title compound. ¹H NMR(400 MHz, chloroform-d) δ ppm 7.05 (d, J=2.2 Hz, 1H), 7.00 (ddt, J=8.2,2.3, 0.8 Hz, 1H), 6.32 (d, J=8.1 Hz, 1H), 5.28-5.20 (m, 1H), 4.95 (ddt,J=6.9, 6.1, 0.8 Hz, 2H), 4.70 (ddt, J=6.9, 5.2, 0.8 Hz, 2H), 3.65 (d,J=0.7 Hz, 3H), 2.28 (d, J=0.7 Hz, 3H), 1.63 (qd, J=4.0, 0.6 Hz, 2H),1.18-1.11 (m, 2H). MS (APCI+) m/z 263 (M+H)⁺.

Example 1-93C1-(5-methyl-2-(oxetan-3-yloxy)phenyl)cyclopropanecarboxylic Acid

Methyl 1-(5-methyl-2-(oxetan-3-yloxy)phenyl)cyclopropanecarboxylate(1.84 g, 7.01 mmol) from Example I-93B was dissolved in tetrahydrofuran(5 mL) and methanol (5 mL) and water (5 mL) water. The mixture wastreated with sodium hydroxide (1.922 g, 48.1 mmol) and stirred at 50° C.for 16 hours. The reaction was reduced in volume, cooled in an ice bathand carefully quenched with concentrated aqueous HCl (˜4 mL, dilutedwith ice) until the pH was acidic. The resulting slurry was stirredvigorously and filtered. The material was washed with water and dried ina vacuum oven overnight to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 9.66 (s, 1H), 7.06 (d, J=2.2 Hz, 1H), 7.00 (dd,J=8.3, 2.2 Hz, 1H), 6.31 (d, J=8.2 Hz, 1H), 5.22 (p, J=5.7 Hz, 1H), 4.95(t, J=6.6 Hz, 2H), 4.74 (dd, J=7.2, 5.3 Hz, 2H), 2.27 (s, 3H), 1.68 (q,J=4.1 Hz, 2H), 1.21 (q, J=4.1 Hz, 2H). MS (ESI−) m/z 247 (M−H)⁻.

Example I-93D1-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(5-methyl-2-(oxetan-3-yloxy)phenyl)cyclopropanecarboxylic acid (66 mg,0.266 mmol) from Example I-93C,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (114 mg, 0.595 mmol) and N,N-dimethylpyridin-4-amine (33mg, 0.270 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (55.4 mg, 0.266 mmol). The reaction was stirredat ambient temperature for 15 hours and was quenched with 0.3 mL of 1Naqueous HCl. The crude material was purified using a 12 g silica gelcartridge with a gradient of 0-10% methanol/dichloromethane and theresulting product triturated with ether then methanol to provide thetitle compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 9.05 (dd, J=4.1,1.6 Hz, 1H), 8.83 (dt, J=8.9, 1.2 Hz, 1H), 8.52 (dd, J=7.5, 1.2 Hz, 1H),8.41 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 7.87 (t, J=8.0 Hz, 1H), 7.55 (dd,J=8.8, 4.2 Hz, 1H), 7.12 (dd, J=8.2, 2.2 Hz, 1H), 7.06 (d, J=2.2 Hz,1H), 6.33 (d, J=8.3 Hz, 1H), 4.96 (p, J=5.5 Hz, 1H), 4.80-4.69 (m, 2H),4.41 (dd, J=7.4, 5.1 Hz, 2H), 2.31 (s, 3H), 1.54 (q, J=4.0 Hz, 2H), 1.05(q, J=4.0 Hz, 2H). MS (ESI−) m/z 437 (M−H)⁻.

Example I-941-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indazole-4-sulfonyl)cyclopropane-1-carboxamide

Example 1-94 was prepared as described in Example 1-26, substituting1-(5-ethyl-2-isobutoxypyridin-3-yl)cyclopropane-1-carboxylic acid forExample I-26B. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆:D₂O=9:1 (v/v)) δppm 8.35 (d, J=1.0 Hz, 1H), 7.98-7.92 (m, 1H), 7.90 (d, J=2.3 Hz, 1H),7.74 (d, J=7.1 Hz, 1H), 7.58 (dd, J=8.4, 7.3 Hz, 1H), 7.43 (d, J=2.3 Hz,1H), 3.74 (d, J=6.4 Hz, 2H), 2.61-2.53 (m, 2H), 1.52-1.40 (m, 1H), 1.37(q, J=4.4 Hz, 2H), 1.20 (t, J=7.6 Hz, 3H), 1.06 (q, J=4.5 Hz, 2H), 0.71(d, J=6.7 Hz, 6H). MS (APCI) m/z 443.0 (M+H)⁺.

Example I-951-(2-{[(2R)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-95A (R)-2-bromo-1-((1-methoxypropan-2-yl)oxy)-4-methylbenzene

In a 100 mL flask was added 2-bromo-4-methylphenol (0.897 g, 4.60 mmol)and triphenylphosphine (1.932 g, 7.37 mmol) in tetrahydrofuran (23.02mL). The mixture was stirred briefly at ambient temperature, undernitrogen, and DIAD (diisopropyl azodicarboxylate, 1.433 mL, 7.37 mmol)was added to the mixture. The mixture was stirred briefly under nitrogenat ambient temperature. (S)-1-Methoxypropan-2-ol (0.415 g, 4.60 mmol)was added dropwise to the solution. The reaction mixture was stirred for16 hours at ambient temperature. The solvent was removed under reducedpressure and the crude material was purified by silica gelchromatography eluting with ethyl acetate in heptanes (0 to 30%) toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.34(dt, J=1.6, 0.8 Hz, 1H), 7.06-6.97 (m, 1H), 6.89 (dd, J=8.3, 5.5 Hz,1H), 4.46 (pd, J=6.2, 4.8 Hz, 1H), 3.63 (dd, J=10.4, 5.9 Hz, 1H), 3.51(dd, J=10.3, 4.7 Hz, 1H), 3.42 (d, J=0.6 Hz, 3H), 2.26 (d, J=0.8 Hz,3H), 1.36-1.30 (m, 3H).

Example I-95B (R)-methyl1-(2-((1-methoxypropan-2-yl)oxy)-5-methylphenyl)cyclopropanecarboxylate

To a solution of(R)-2-bromo-1-((1-methoxypropan-2-yl)oxy)-4-methylbenzene (0.350 g,1.351 mmol) from Example I-95A in tetrahydrofuran (4 mL) was addedbis(dibenzylideneacetone)palladium (0.016 g, 0.027 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.019 g,0.027 mmol). Nitrogen was bubbled through the solution for about 3minutes, then a 0.54 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (5.00 mL, 2.70 mmol)was added dropwise over 5 minutes. The reaction was stirred for 5 hoursat ambient temperature and 3 mL additional ZnBr reagent was added andthe reaction was stirred at ambient temperature for 16 hours. Thereaction was quenched with saturated aqueous ammonium chloride (25 mL),diluted with methyl tert-butyl ether (200 mL), and the layers wereseparated. The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified via flashchromatography, eluting on a 24 g silica gel cartridge with 0-50% ethylacetate/hexanes over 20 minutes to provide the title compound. ¹H NMR(501 MHz, chloroform-d) δ ppm 7.08-6.99 (m, 2H), 6.82 (d, J=8.2 Hz, 1H),4.56 (h, J=5.9 Hz, 1H), 3.62 (s, 3H), 3.59 (dd, J=10.2, 5.7 Hz, 1H),3.45 (dd, J=10.2, 5.1 Hz, 1H), 3.42 (s, 3H), 2.30 (s, 3H), 1.61-1.57 (m,2H), 1.29 (d, J=6.2 Hz, 3H), 1.16-1.09 (m, 2H).

Example 1-95C(R)-1-(2-((1-methoxypropan-2-yl)oxy)-5-methylphenyl)cyclopropanecarboxylicAcid

(R)-Methyl1-(2-((1-methoxypropan-2-yl)oxy)-5-methylphenyl)cyclopropanecarboxylate(0.251 g, 0.902 mmol) from Example I-95B was dissolved intetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL). The mixturewas treated with sodium hydroxide (0.185 g, 4.63 mmol) and stirred at70° C. for 45 minutes. The reaction was reduced in volume, cooled in anice bath and carefully quenched with concentrated aqueous HCl (about 4mL, diluted with ice) until the pH was acidic. The resulting materialwas stirred vigorously and the water was decanted. The material waswashed with water and azeotroped with toluene to provide the titlecompound. ¹H NMR (500 MHz, chloroform-d) δ ppm 8.13 (s, 1H), 7.03 (d,J=7.2 Hz, 2H), 6.84-6.74 (m, 1H), 4.55 (td, J=6.3, 4.8 Hz, 1H), 3.59(dd, J=10.2, 6.1 Hz, 1H), 3.43 (dd, J=10.2, 4.7 Hz, 1H), 3.36 (s, 3H),2.28 (s, 3H), 1.67-1.56 (m, 2H), 1.26 (d, J=6.2 Hz, 3H), 1.18 (dt,J=8.5, 2.5 Hz, 1H), 1.11-1.02 (m, 1H). MS (ESI−) m/z 263 (M−H)⁻.

Example I-95D1-(2-{[(2R)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(R)-1-(2-((1-methoxypropan-2-yl)oxy)-5-methylphenyl)cyclopropanecarboxylicacid (59 mg, 0.223 mmol) from Example I-95C,Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (96 mg, 0.501 mmol) and N,N-dimethylpyridin-4-amine (28mg, 0.229 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (46.5 mg, 0.223 mmol). The reaction was stirredat ambient temperature for 16 hours and was quenched with 0.3 mL of 1Naqueous HCl. The crude material was purified using a 12 g silica gelcartridge with a gradient of 0-10% methanol/dichloromethane and theresulting product triturated with ether then a scant amount of methanolto provide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.99(dd, J=4.2, 1.6 Hz, 1H), 8.76 (ddd, J=8.7, 1.7, 0.9 Hz, 1H), 8.70 (s,1H), 8.49 (dd, J=7.5, 1.2 Hz, 1H), 8.38 (dt, J=8.5, 1.1 Hz, 1H), 7.83(dd, J=8.5, 7.5 Hz, 1H), 7.44 (dd, J=8.8, 4.2 Hz, 1H), 7.14 (ddd, J=8.4,2.3, 0.8 Hz, 1H), 6.94-6.92 (m, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.56 (pd,J=6.2, 4.5 Hz, 1H), 3.46 (dd, J=10.1, 6.1 Hz, 1H), 3.40-3.36 (m, 1H),3.36 (s, 3H), 2.26 (s, 3H), 1.53-1.45 (m, 1H), 1.45-1.36 (m, 1H), 1.24(d, J=6.2 Hz, 3H), 1.00 (td, J=3.7, 2.2 Hz, 2H). MS (ESI−) m/z 437(M−H)⁻.

Example I-96N-(2-aminoquinoline-5-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamideExample I-96AN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(2-isobutoxy-5-methylpyridin-3-yl)cyclopropanecarboxamide

To a solution of1-(2-isobutoxy-5-methylpyridin-3-yl)cyclopropanecarboxylic acid (35 mg,0.140 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (65 mg, 0.339 mmol) and N,N-dimethylpyridin-4-amine (20mg, 0.164 mmol) in anhydrous dichloromethane (1 mL) was added2-(diallylamino)quinoline-5-sulfonamide (52 mg, 0.171 mmol) from ExampleI-87D. The reaction was stirred at ambient temperature for 16 hours. Thereaction was quenched with 0.3 mL of aqueous 1N HCl and purified using a12 g silica gel cartridge with a gradient of 5-100% ethylacetate/hexanes over 20 minutes to provide the title compound. MS(APCI+) m/z 535 (M+H)⁺.

Example I-96BN-(2-aminoquinoline-5-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide

A solution of ethanol (0.5 mL) and water (0.5 mL) was degassed bybubbling nitrogen through for 15 minutes. The mixture was added to amixture ofN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(2-isobutoxy-5-methylpyridin-3-yl)cyclopropanecarboxamide(73 mg, 0.137 mmol) from Example I-96A and RhCl(PPh₃)₃ (Wilkinson'scatalyst, chloridotris(triphenylphosphane)rhodium(I), 4.3 mg, 4.65 μmol)under nitrogen. The reaction was heated at 100° C. for 4 hours. Thereaction was cooled and filtered and the resulting material was purifiedby reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.75 (s, 1H), 8.84 (s, 2H), 8.79 (d, J=9.9 Hz, 1H), 8.01 (dd,J=6.9, 1.8 Hz, 1H), 7.93-7.84 (m, 2H), 7.82 (dd, J=2.3, 1.0 Hz, 1H),7.36 (d, J=2.3 Hz, 1H), 7.12 (d, J=9.8 Hz, 1H), 3.66 (d, J=6.5 Hz, 2H),2.17 (s, 3H), 1.41 (hept, J=6.6 Hz, 1H), 1.31 (q, J=4.3 Hz, 2H), 0.97(q, J=4.4 Hz, 2H), 0.67 (d, J=6.7 Hz, 6H). MS (APCI+) m/z 455 (M+H)⁺.

Example I-97N-(2-aminoquinoline-5-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide

To a solution of1-(2-isopropoxy-5-methylpyridin-3-yl)cyclopropanecarboxylic acid (35 mg,0.149 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (65 mg, 0.339 mmol) and N,N-dimethylpyridin-4-amine (25mg, 0.205 mmol) in anhydrous dichloromethane (1 mL) was added2-(diallylamino)quinoline-5-sulfonamide (47 mg, 0.155 mmol) from ExampleI-87D. The reaction was stirred at ambient temperature for 15 hours. Thereaction was quenched with 0.3 mL of aqueous 1N HCl and was purifiedusing a 12 g silica gel cartridge with a gradient of 5-100% ethylacetate/hexanes over 20 minutes to provideN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(2-isopropoxy-5-methylpyridin-3-yl)cyclopropanecarboxamide.TheN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(2-isopropoxy-5-methylpyridin-3-yl)cyclopropanecarboxamidewas combined with RhCl(PPh₃)₃ (Wilkinson's catalyst,chloridotris(triphenylphosphane)rhodium(I), 3.2 mg, 3.46 μmol) in adegassed solution of ethanol (0.5 mL) and water (0.5 mL) under nitrogen.The reaction was heated at 100° C. for 4 hours. The reaction was cooledand filtered and the resulting material was purified by reverse-phasepreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column(30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to providethe title compound as a trifluoroacetic acid salt. ¹H NMR (501 MHz,dimethyl sulfoxide-d₆) δ ppm 11.73 (s, 1H), 9.07 (s, 2H), 8.91 (d, J=9.8Hz, 1H), 8.05 (dd, J=6.9, 1.9 Hz, 1H), 7.95-7.88 (m, 2H), 7.87 (dd,J=2.3, 1.0 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.18 (d, J=9.8 Hz, 1H), 5.06(hept, J=6.1 Hz, 1H), 2.18 (s, 3H), 1.27 (q, J=4.3 Hz, 2H), 1.07 (d,J=6.1 Hz, 6H), 0.99 (q, J=4.4 Hz, 2H). MS (APCI+) m/z 441 (M+H)⁺.

Example I-98N-(2-aminoquinoline-5-sulfonyl)-1-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide

To a solution of1-(5-ethyl-2-isobutoxypyridin-3-yl)cyclopropanecarboxylic acid (35 mg,0.133 mmol),N₁-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (58 mg, 0.303 mmol) and N,N-dimethylpyridin-4-amine (25mg, 0.205 mmol) in anhydrous dichloromethane (1 mL) was added2-(diallylamino)quinoline-5-sulfonamide (46 mg, 0.152 mmol) from ExampleI-87D. The reaction was stirred at ambient temperature for 15 hours. Thereaction was quenched with 0.2 mL of aqueous 1N HCl and purified using a12 g silica gel cartridge with a gradient of 5-100% ethylacetate/hexanes over 20 minutes to provideN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(5-ethyl-2-isobutoxypyridin-3-yl)cyclopropanecarboxamide.TheN-((2-(diallylamino)quinolin-5-yl)sulfonyl)-1-(5-ethyl-2-isobutoxypyridin-3-yl)cyclopropanecarboxamidewas combined with RhCl(PPh₃)₃ (Wilkinson's catalyst,chloridotris(triphenylphosphane)rhodium(I), 3.2 mg, 3.46 μmol) in adegassed solution of ethanol (0.5 mL) and water (0.5 mL) under nitrogen.The reaction was heated to 100° C. for 4 hours. The reaction was cooledand filtered and the resulting material was purified by reverse-phasepreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column(30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to providethe title compound as a trifluoroacetic acid salt. ¹H NMR (501 MHz,dimethyl sulfoxide-d₆) δ ppm 11.49 (s, 1H), 8.84 (s, 2H), 8.80 (d, J=9.7Hz, 1H), 8.01 (dd, J=7.2, 1.7 Hz, 1H), 7.93-7.86 (m, 2H), 7.85 (d, J=2.3Hz, 1H), 7.39 (d, J=2.4 Hz, 1H), 7.13 (d, J=9.8 Hz, 1H), 3.68 (d, J=6.5Hz, 2H), 2.55-2.50 (m, 2H), 1.42 (hept, J=6.6 Hz, 1H), 1.35 (q, J=4.3Hz, 2H), 1.16 (t, J=7.6 Hz, 3H), 1.01 (q, J=4.4 Hz, 2H), 0.68 (d, J=6.7Hz, 6H). MS (APCI+) m/z 469 (M+H)⁺.

Example I-991-[2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl)cyclopropanecarboxylic acid(60 mg, 0.205 mmol) from Example I-103E,Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (79 mg, 0.410 mmol) and N,N-dimethylpyridin-4-amine (27.6mg, 0.226 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (42.7 mg, 0.205 mmol). After 16 hours, thereaction was quenched with 1 mL of 1N aqueous citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 10 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. The crudematerial was triturated with methanol (0.5 mL) and filtered to providethe title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.48(s, 1H), 9.05 (dd, J=4.2, 1.6 Hz, 1H), 8.95 (d, J=8.7 Hz, 1H), 8.34 (d,J=8.6 Hz, 1H), 8.31 (d, J=7.6 Hz, 1H), 7.93 (t, J=7.9 Hz, 1H), 7.68 (dd,J=8.8, 4.1 Hz, 1H), 7.22 (dd, J=8.5, 2.3 Hz, 1H), 7.08 (d, J=2.4 Hz,1H), 6.77 (d, J=8.5 Hz, 1H), 3.64 (q, J=6.9 Hz, 2H), 3.12 (q, J=7.0 Hz,2H), 1.42 (s, 6H), 1.33 (q, J=4.4 Hz, 2H), 1.03 (t, J=6.9 Hz, 3H), 0.94(q, J=4.6 Hz, 2H), 0.74 (t, J=6.9 Hz, 3H). MS (ESI−) m/z 481 (M−H)⁻.

Example I-1001-[2-(difluoromethoxy)-5-methylphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-100A 2-bromo-4-chloro-1-(difluoromethoxy)benzene

2-Bromo-4-chlorophenol (3.82 g, 18.4 mmol) was dissolved in acetonitrile(92 mL). The resulting suspension was cooled to <−25° C. in anacetone-dry ice bath and diethyl (bromodifluoromethyl)phosphonate (4.91mL, 27.6 mmol) was added, followed by dropwise addition of potassiumhydroxide (20.66 g, 368 mmol) at such a rate that the temperature wasmaintained below −15° C. After the addition was complete (<5 minutes),the reaction was stirred for an additional 15 minutes and warmed toambient temperature. The reaction was diluted with methyl tert-butylether, washed three times with water, once with brine, and concentrated.The crude material was purified silica gel chromatography, eluting with0-10% ethyl acetate/heptanes over 20 minutes to provide the titlecompound. ¹H NMR (500 MHz, chloroform-d) δ ppm 7.67 (d, J=2.5 Hz, 1H),7.34 (dd, J=8.7, 2.5 Hz, 1H), 7.21 (dt, J=8.7, 0.9 Hz, 1H), 6.55 (t,J=73.0 Hz, 1H).

Example I-100B Methyl1-(5-chloro-2-(difluoromethoxy)phenyl)cyclopropanecarboxylate

To a solution of 2-bromo-4-chloro-1-(difluoromethoxy)benzene (0.887 g,3.45 mmol) from Example I-100A in tetrahydrofuran (10 mL) was addedbis(dibenzylideneacetone)palladium (0.040 g, 0.069 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.049 g,0.069 mmol). Nitrogen was bubbled through the solution for about 3minutes, and a 0.54 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (12.76 mL, 6.89 mmol)was added dropwise over 5 minutes. The reaction was stirred for 15 hoursat ambient temperature. The reaction was quenched with saturated aqueousammonium chloride (25 mL), diluted with methyl tert-butyl ether (200mL), and the layers were separated. The organic layer was dried oversodium sulfate, filtered and concentrated in vacuo to give a crudematerial that was purified via flash chromatography, eluting on a 24 gsilica gel cartridge with 0-50% ethyl acetate/hexanes over 20 minutes toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm7.29-7.25 (m, 2H), 7.12-7.04 (m, 1H), 6.45 (t, J=73.8 Hz, 1H), 3.64 (s,3H), 1.72-1.65 (m, 2H), 1.22-1.13 (m, 2H).

Example I-100C Methyl1-(2-(difluoromethoxy)-5-methylphenyl)cyclopropanecarboxylate

A solution of methyl1-(5-chloro-2-(difluoromethoxy)phenyl)cyclopropanecarboxylate (260 mg,0.940 mmol) from Example I-100B and PEPPSI IPentCl (17 mg, 0.020 mmol)in tetrahydrofuran (1 mL) was purged with nitrogen for 5 minutes.Dimethylzinc (1.880 mL, 1.880 mmol), 1M in tetrahydrofuran, was addeddropwise. After 30 minutes, additional dimethylzinc solution was added(1 mL, 1 mmol). The reaction was stirred overnight at ambienttemperature. The reaction was warmed to 50° C. After 4 hours, thereaction was cooled, quenched with 15 mL of saturated aqueous ammoniumchloride, and diluted with 150 mL of methyl tert-butyl ether. Theorganics were separated, washed with brine, dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was purifiedusing a 12 g silica gel cartridge with a gradient of 5-50% ethylacetate/hexanes over 20 minutes to provide the title compound. ¹H NMR(400 MHz, Chloroform-d) δ ppm 7.10 (dd, J=6.4, 2.2 Hz, 2H), 7.02 (dt,J=8.8, 1.0 Hz, 1H), 6.44 (td, J=74.5, 0.8 Hz, 1H), 3.63 (s, 3H), 2.33(s, 3H), 1.71-1.64 (m, 2H), 1.18 (q, J=4.3 Hz, 2H).

Example I-100D1-[2-(difluoromethoxy)-5-methylphenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-(difluoromethoxy)-5-methylphenyl)cyclopropanecarboxylic acid (58mg, 0.239 mmol) from Example I-100C,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (92 mg, 0.479 mmol) and N,N-dimethylpyridin-4-amine (29.3mg, 0.239 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (70 mg, 0.336 mmol). The reaction was stirred atambient temperature for 15 hours. The reaction was quenched with 0.3 mLof 1 N aqueous HCl and extracted with dichloromethane (3×1 mL). Theextracts were concentrated and the crude material was purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100AAXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound as a trifluoroacetic acid salt. ¹H NMR(400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.64 (s, 1H), 9.03 (dd, J=4.2,1.6 Hz, 1H), 8.98 (dt, J=8.8, 1.2 Hz, 1H), 8.31 (dt, J=8.4, 1.0 Hz, 1H),8.28 (dd, J=7.5, 1.2 Hz, 1H), 7.89 (dd, J=8.4, 7.5 Hz, 1H), 7.70 (dd,J=8.8, 4.2 Hz, 1H), 7.14-7.09 (m, 1H), 7.06 (d, J=2.1 Hz, 1H), 6.91 (d,J=8.2 Hz, 1H), 6.71 (t, J=74.4 Hz, 1H), 2.23 (s, 3H), 1.34 (q, J=4.5 Hz,2H), 1.03 (q, J=4.6 Hz, 2H). MS (ESI−) m/z 431 (M−H)⁻.

Example I-1011-[2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-101A Methyl 2-(4-ethoxyphenyl)-2-methylpropanoate

A solution of freshly-prepared(1-methoxy-2-methyl-1-oxopropan-2-yl)zinc(II) bromide (146 mL, 21.93mmol) was made by treating a suspension of zinc (5.42 g, 83 mmol) intetrahydrofuran (153 mL) with bromine (0.569 mL, 11.05 mmol) andtreating the ambient temperature solution with dropwise addition ofmethyl 2-bromo-2-methylpropanoate (10.0 g, 55.2 mmol) with stirring atambient temperature for 2 hours. 1-Bromo-4-ethoxybenzene (2.132 mL,14.62 mmol) was dissolved in tetrahydrofuran (58.5 mL), and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.208 g,0.292 mmol) and bis(dibenzylideneacetone)palladium (0.168 g, 0.292 mmol)were added. The solution of freshly prepared(1-methoxy-2-methyl-1-oxopropan-2-yl)zinc(II) bromide (146 mL, 21.93mmol) was added dropwise maintaining a slight exotherm of ˜3° C. Thereaction was stirred for 60 minutes at ambient temperature, quenchedwith saturated aqueous ammonium chloride (0.5 mL), and diluted withmethyl tert-butyl ether. The organic layer was concentrated in vacuo.The residue was loaded directly onto a 120 g silica gel column and waseluted with 0-20% ethyl acetate/heptanes to provide the title compound.¹H NMR (400 MHz, chloroform-d) δ ppm 7.26 (d, J=8.8 Hz, 2H), 6.85 (d,J=8.9 Hz, 2H), 4.03 (q, J=7.0 Hz, 2H), 3.65 (s, 3H), 1.43-1.38 (m, 9H).MS (ESI+) m/z 222 (M+H)⁺.

Example I-101B Methyl 2-(3-bromo-4-ethoxyphenyl)-2-methylpropanoate

A solution of methyl 2-(4-ethoxyphenyl)-2-methylpropanoate (1.35 g, 6.07mmol) from Example I-101A in acetonitrile (20.24 mL) was treated withN-bromosuccinimide (1.135 g, 6.38 mmol) and stirred at ambienttemperature for 2 hours. The reaction was diluted with 200 mL of methyltert-butyl ether, and quenched with 100 mL of 5% aqueous NaOH solution.The organic layer was separated, washed with saturated aqueous sodiumbicarbonate and brine, dried over sodium sulfate, filtered, concentratedto ˜20 mL, and filtered again. The filtrate was concentrated andpurified by silica gel chromatography, eluting with ethyl acetate inheptanes (0 to 30%) to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.51 (dd, J=2.4, 0.6 Hz, 1H), 7.29-7.17 (m, 1H),6.83 (d, J=8.6 Hz, 1H), 4.08 (q, J=7.0 Hz, 2H), 3.65 (d, J=0.6 Hz, 3H),1.55 (s, 6H), 1.45 (td, J=7.0, 0.6 Hz, 3H).

Example I-101C 2-(3-bromo-4-ethoxyphenyl)-2-methylpropan-1-ol

To a cooled (<5° C.) solution of methyl2-(3-bromo-4-ethoxyphenyl)-2-methylpropanoate (1.25 g, 4.15 mmol) fromExample I-101B in tetrahydrofuran (8.30 mL) was added a solution of 1 Mlithium aluminum hydride (2.91 mL, 2.91 mmol) in tetrahydrofuran over 10minutes, maintaining an internal temperature <10° C. After 1 hour, andthe reaction was quenched by the addition of 1.5 mL of acetone, dilutedwith ethyl acetate and stirred with 50 mL of saturated aqueousRochelle's salt until two clear layers were present. The aqueous layerwas extracted with ethyl acetate and the combined extracts were washedwith brine, dried over sodium sulfate, filtered and concentrated toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.54(d, J=2.4 Hz, 1H), 7.25 (dd, J=8.6, 2.4 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H),4.09 (q, J=7.0 Hz, 2H), 3.57 (s, 2H), 1.46 (t, J=7.0 Hz, 3H), 1.30 (s,6H), 1.04-0.85 (m, 1H).

Example I-101D 2-bromo-1-ethoxy-4-(1-methoxy-2-methylpropan-2-yl)benzene

To a cooled (ice bath) solution of2-(3-bromo-4-ethoxyphenyl)-2-methylpropan-1-ol (1.1 g, 4.03 mmol) fromExample I-101C in tetrahydrofuran (8.05 mL) was added sodium hydride(0.242 g, 6.04 mmol) and the reaction was stirred at 5° C. for one hour.Iodomethane (0.501 mL, 8.05 mmol) was added and the reaction was allowedto warm to ambient temperature and stir for 16 hours. Water was addedslowly to quench the reaction and the solution was diluted with methyltert-butyl ether (30 mL). The organic layer was separated, dried oversodium sulfate, filtered and concentrated. The residue was purified bysilica gel chromatography eluting with ethyl acetate in heptanes (0 to20%) to provide the title compound. ¹H NMR (500 MHz, chloroform-d) δ ppm7.55 (d, J=2.4 Hz, 1H), 7.27 (dd, J=8.6, 2.4 Hz, 1H), 6.85 (d, J=8.6 Hz,1H), 4.11 (q, J=7.0 Hz, 2H), 3.36 (s, 2H), 3.33 (s, 3H), 1.48 (t, J=7.0Hz, 3H), 1.31 (s, 6H).

Example I-101E Methyl1-(2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropanecarboxylate

To a solution of2-bromo-1-ethoxy-4-(1-methoxy-2-methylpropan-2-yl)benzene (0.80 g, 2.79mmol) from Example I-101D in tetrahydrofuran (4 mL) was addedbis(dibenzylideneacetone)palladium (0.032 g, 0.056 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.040 g,0.056 mmol). Nitrogen was bubbled through the solution for about 10minutes. A tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (0.45M, 12.38 mL, 5.57mmol) was added dropwise over 5 minutes and the temperature slowlyincreased from 19-23° C. The reaction was stirred for 3 hours at ambienttemperature, and additional (1-(methoxycarbonyl)cyclopropyl)zinc(II)bromide (12.38 mL, 5.57 mmol) was added and the reaction was stirred atambient temperature for 16 hours. The reaction was quenched withsaturated aqueous ammonium chloride (50 mL) and diluted with methyltert-butyl ether (400 mL). The organics were separated, washed withbrine, dried over sodium sulfate, and filtered. The solvent was removedin vacuo and the crude material was purified, eluting on a 40 g silicagel cartridge with 0-50% ethyl acetate/hexanes over 20 minutes toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.24(dd, J=8.5, 2.6 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H),4.04 (q, J=7.0 Hz, 2H), 3.61 (s, 3H), 3.36 (s, 2H), 3.32 (s, 3H), 1.60(q, J=4.1 Hz, 2H), 1.37 (t, J=6.9 Hz, 3H), 1.31 (s, 6H), 1.12 (q, J=4.1Hz, 2H). MS (ESI+) m/z 307 (M+H)⁺.

Example I-101F1-(2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropanecarboxylicAcid

Methyl1-(2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropanecarboxylate(0.843 g, 2.75 mmol) from Example I-101E was dissolved intetrahydrofuran (4 mL), methanol (4 mL), and water (4 mL). The mixturewas treated with sodium hydroxide (0.569 g, 14.23 mmol) and stirred at50° C. for 15 hours. The reaction was concentrated, cooled in an icebath and carefully quenched with 2N aqueous citric acid (about 8 mL)until the pH ˜5. The resulting emulsion was stirred vigorously, theaqueous layer was removed, and the organic layer was washed with water(2×0.3 mL). The mixture was dried via azeotrope with toluene to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.24 (dd,J=8.5, 2.5 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 4.05(q, J=7.0 Hz, 2H), 3.34 (s, 3H), 3.30 (s, 2H), 1.64 (q, J=4.0 Hz, 2H),1.38 (t, J=7.0 Hz, 3H), 1.30 (s, 6H), 1.17 (q, J=4.1 Hz, 2H). MS (ESI−)m/z 290.9 (M−H)⁻.

Example I-101G1-[2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-ethoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropanecarboxylicacid (72 mg, 0.246 mmol) from Example I-101F,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (94 mg, 0.493 mmol) and N,N-dimethylpyridin-4-amine (30.1mg, 0.246 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (56 mg, 0.269 mmol). The reaction was stirred atambient temperature for 16 hours. The reaction was quenched with 0.2 mLof aqueous 2N citric acid and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes. The crudematerial was triturated with diethyl ether and filtered to provide thetitle compound. ¹H NMR (501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.42 (s,1H), 9.03 (dd, J=4.1, 1.6 Hz, 1H), 8.94 (dt, J=8.7, 1.1 Hz, 1H), 8.32(d, J=8.5 Hz, 1H), 8.29 (d, J=7.4 Hz, 1H), 7.91 (t, J=7.9 Hz, 1H), 7.67(dd, J=8.8, 4.2 Hz, 1H), 7.18 (dd, J=8.6, 2.5 Hz, 1H), 7.05 (d, J=2.5Hz, 1H), 6.71 (d, J=8.6 Hz, 1H), 3.60 (q, J=6.9 Hz, 2H), 3.28 (s, 2H),3.20 (s, 3H), 1.30 (q, J=4.4 Hz, 2H), 1.20 (s, 6H), 0.93 (q, J=4.4 Hz,2H), 0.69 (t, J=6.9 Hz, 3H). MS (ESI−) m/z 481 (M−H)⁻.

Example I-1021-[2-ethoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-102A 1-(4-ethoxyphenyl)cyclobutanol

To a cooled (ice/NaCl bath) solution of 1M (4-ethoxyphenyl)magnesiumbromide (50 mL, 50.0 mmol) was added cyclobutanone (3.25 g, 45.5 mmol)dropwise, keeping the internal temperature below 0° C. The reaction wasallowed to slowly warm to ambient temperature and was stirred for 5hours. The reaction was cooled in an ice bath and was quenched withsaturated aqueous ammonium chloride (100 mL) and diluted with methyltert-butyl ether (200 mL). The organic layer was separated, dried oversodium sulfate, filtered and concentrated in vacuo. The crude materialwas purified by silica gel chromatography, eluting with ethyl acetate inheptanes (0 to 20%) to provide the title compound. ¹H NMR (501 MHz,chloroform-d) δ ppm 7.44-7.37 (m, 2H), 6.92-6.85 (m, 2H), 3.80 (s, 3H),2.57-2.47 (m, 2H), 2.34 (tdd, J=9.5, 7.7, 3.0 Hz, 2H), 2.19 (s, 1H),2.05-1.90 (m, 1H), 1.63 (dddd, J=16.4, 11.2, 8.7, 7.7 Hz, 1H).

Example I-102B 1-ethoxy-4-(1-methoxycyclobutyl)benzene

To a cooled (ice bath) solution of 1-(4-ethoxyphenyl)cyclobutanol (8.74g, 45.5 mmol) from Example I-102A in tetrahydrofuran (91 mL) was addedsodium hydride (3.09 g, 77 mmol) and the reaction was stirred at 5° C.for one hour. Iodomethane (6.23 mL, 100 mmol) was added and the reactionwas allowed to warm to ambient temperature and stir for 18 hours. Waterwas added slowly to quench the reaction and the solution was dilutedwith methyl tert-butyl ether (300 mL). The organic layer was separated,dried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by silica gel chromatography, elutingwith ethyl acetate in heptanes (0 to 20%) to provide the title compound.¹H NMR (400 MHz, chloroform-d) δ ppm 7.37-7.29 (m, 2H), 6.93-6.85 (m,2H), 4.04 (q, J=7.0 Hz, 2H), 2.91 (s, 3H), 2.44-2.26 (m, 4H), 1.92 (dtd,J=11.1, 9.1, 4.6 Hz, 1H), 1.72-1.55 (m, 1H), 1.42 (t, J=7.0 Hz, 3H).

Example I-102C 2-bromo-1-ethoxy-4-(1-methoxycyclobutyl)benzene

A solution of 1-ethoxy-4-(1-methoxycyclobutyl)benzene (0.47 g, 2.278mmol) from Example I-102B in acetonitrile (7.59 mL) was treated with NBS(N-bromosuccinimide, 0.426 g, 2.392 mmol), stirred at ambienttemperature for 18 hours, and heated to 40° C. for 3 hours. The reactionwas cooled to ambient temperature, diluted with 20 mL of methyltert-butyl ether, and quenched with 10 mL of 5% aqueous NaOH. Theorganic layer was washed with saturated aqueous sodium bicarbonate andbrine, dried over sodium sulfate, filtered, concentrated to ˜20 mL, andfiltered again. The filtrate was concentrated and purified by silica gelchromatography, eluting with ethyl acetate in heptanes (0 to 30%) toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.60(d, J=2.2 Hz, 1H), 7.31 (dd, J=8.5, 2.2 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H),4.13 (q, J=7.0 Hz, 2H), 2.93 (s, 3H), 2.43-2.29 (m, 2H), 2.01-1.86 (m,1H), 1.73-1.58 (m, 2H), 1.49 (t, J=7.0 Hz, 3H), 1.44 (td, J=6.9, 3.9 Hz,1H).

Example I-102D Methyl1-(2-ethoxy-5-(1-methoxycyclobutyl)phenyl)cyclopropanecarboxylate

To a solution of 2-bromo-1-ethoxy-4-(1-methoxycyclobutyl)benzene (230mg, 0.807 mmol) from Example I-102C in tetrahydrofuran (2 mL) was addedbis(dibenzylideneacetone)palladium (9.28 mg, 0.016 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (11.46 mg,0.016 mmol). Nitrogen was bubbled through the solution for about 10minutes. A tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (0.45 M, 4 mL, 1.800mmol) was added dropwise over 5 minutes and the temperature slowlyincreased from 19-23° C. The reaction was stirred for 4 hours at ambienttemperature. Additional (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide(2 mL, 0.90 mmol) was added and the reaction was stirred at ambienttemperature for 72 hours. The reaction was quenched with saturatedaqueous ammonium chloride (15 mL) and diluted with methyl tert-butylether (100 mL). The organics were separated, washed with brine, driedover sodium sulfate and filtered. The solvent was removed in vacuo andthe crude material was purified on a 24 g silica gel cartridge with0-50% ethyl acetate/hexanes over 20 minutes to provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.31-7.22 (m, 2H), 6.83(d, J=8.3 Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 3.61 (s, 3H), 2.92 (s, 3H),2.44-2.29 (m, 4H), 1.94 (dtd, J=11.1, 9.1, 4.7 Hz, 1H), 1.74-1.64 (m,1H), 1.61 (q, J=4.1 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H), 1.13 (q, J=4.1 Hz,2H).

Example I-102E1-(2-ethoxy-5-(1-methoxycyclobutyl)phenyl)cyclopropanecarboxylic Acid

Methyl 1-(2-ethoxy-5-(1-methoxycyclobutyl)phenyl)cyclopropanecarboxylate(0.160 g, 0.526 mmol) from Example I-102D was dissolved intetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL) and treatedwith sodium hydroxide (0.122 g, 3.05 mmol) and stirred at 70° C. for 2hours. The reaction mixture was concentrated, cooled in an ice bath andcarefully quenched with 2N aqueous citric acid (about 1.5 mL) until thepH ˜5. The water was removed by filtration and the material was washedwith water and dried under a stream of nitrogen to provide the titlecompound. ¹H NMR (501 MHz, chloroform-d) δ ppm 11.40 (s, 1H), 7.33-7.25(m, 2H), 6.85 (d, J=8.4 Hz, 1H), 4.09 (q, J=7.0 Hz, 2H), 2.92 (s, 3H),2.44-2.30 (m, 4H), 1.94 (dtt, J=11.1, 9.4, 4.9 Hz, 1H), 1.76-1.58 (m,3H), 1.42 (t, J=6.9 Hz, 3H), 1.21 (q, J=4.1 Hz, 2H). MS (ESI−) m/z 288.9(M−H)⁻.

Example I-102F1-[2-ethoxy-5-(1-methoxycyclobutyl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-ethoxy-5-(1-methoxycyclobutyl)phenyl)cyclopropanecarboxylic acid(72 mg, 0.248 mmol) from Example I-102E,Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (95 mg, 0.496 mmol) and N,N-dimethylpyridin-4-amine (30.3mg, 0.248 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (55 mg, 0.264 mmol). The reaction was stirred atambient temperature for 16 hours. The reaction was quenched with 0.2 mLof 2N aqueous citric acid and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes. The crudematerial was triturated with diethyl ether and filtered to provide thetitle compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.49 (s,1H), 9.01 (dd, J=4.2, 1.6 Hz, 1H), 8.91 (dt, J=8.8, 1.2 Hz, 1H),8.35-8.23 (m, 2H), 7.90 (dd, J=8.4, 7.5 Hz, 1H), 7.64 (dd, J=8.8, 4.2Hz, 1H), 7.21 (dd, J=8.4, 2.3 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.78 (d,J=8.5 Hz, 1H), 3.62 (q, J=7.0 Hz, 2H), 2.78 (s, 3H), 2.34-2.11 (m, 4H),1.81 (ddq, J=11.0, 9.3, 4.8 Hz, 1H), 1.54 (dp, J=10.9, 8.3 Hz, 1H), 1.29(q, J=4.4 Hz, 2H), 0.92 (q, J=4.5 Hz, 2H), 0.71 (t, J=6.9 Hz, 3H). MS(ESI−) m/z 479 (M−H)⁻.

Example I-1031-[2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-103A 1-(3-bromo-4-ethoxyphenyl)ethanone

To a solution of 1-(4-ethoxyphenyl)ethanone (10 g, 60.9 mmol) inmethanol (70 mL) and water (7 mL) was added dibromine (3.28 mL, 63.9mmol) dropwise and the mixture was stirred at ambient temperature for 16hours. The solvent was removed and the reaction was diluted with water(20 mL), and extracted with dichloromethane. The organic layer wasconcentrated in vacuo. The mixture was purified on 40 g silica gelcartridge with 100% dichloromethane over a period of 10 minutes toprovide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 8.19(d, J=2.2 Hz, 1H), 7.92 (dd, J=8.6, 2.2 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H),4.21 (q, J=7.0 Hz, 2H), 2.58 (s, 3H), 1.54 (t, J=7.0 Hz, 3H). MS (APCI+)m/z 243 (M+H)⁺.

Example I-103B 2-(3-bromo-4-ethoxyphenyl)propan-2-ol

To a solution of methylmagnesium bromide in diethyl ether (2.98 mL, 8.93mmol) and tetrahydrofuran (3 mL) at −30° C. was added dropwise1-(3-bromo-4-ethoxyphenyl)ethanone (1.55 g, 6.38 mmol) from ExampleI-103A in dichloromethane (6 mL). The reaction mixture was stirred for90 minutes at −15° C., and 1 hour at −5° C. The mixture was quenchedwith acetic acid (0.548 mL, 9.56 mmol), diluted with 30 mL of water andextracted with dichloromethane. The solvent was evaporated in vacuo andthe resulting residue was purified on a 40 g silica gel cartridgeeluting with a gradient 0-100% ethyl acetate/heptanes over a period of10 minutes to provide the title compound. ¹H NMR (400 MHz, chloroform-d)δ ppm 7.67 (d, J=2.4 Hz, 1H), 7.35 (dd, J=8.5, 2.4 Hz, 1H), 6.85 (d,J=8.6 Hz, 1H), 4.10 (q, J=7.0 Hz, 2H), 1.67 (s, 1H), 1.55 (s, 6H), 1.46(t, J=7.0 Hz, 3H). MS (APCI+) m/z 241 (M+H-H₂O)⁺.

Example I-103C 2-bromo-1-ethoxy-4-(2-ethoxypropan-2-yl)benzene

To a solution of 2-(3-bromo-4-ethoxyphenyl)propan-2-ol (400 mg, 1.544mmol) from Example I-103B in N,N-dimethylformamide (3 mL) at 0° C. wasadded sodium hydride (154 mg, 3.86 mmol). After 30 minutes, iodoethane(481 mg, 3.09 mmol) was added and the reaction was stirred at 20° C. for16 hours. The mixture was quenched via addition of saturated aqueousammonium chloride (80 mL) and extracted with dichloromethane. The crudematerial was purified on 12 g silica gel cartridge with a gradient of0-60% ethyl acetate/heptanes over a period of 10 minutes to provide thetitle compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.57 (d, J=2.3 Hz,1H), 7.28 (dd, J=8.5, 2.3 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.10 (q,J=7.0 Hz, 2H), 3.19 (q, J=7.0 Hz, 2H), 1.49 (s, 6H), 1.47 (t, J=7.0 Hz,3H), 1.14 (t, J=7.0 Hz, 3H). MS (APCI+) m/z 241 (M+H-CH₃CH₂OH)⁺.

Example I-103D Methyl1-(2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl)cyclopropanecarboxylate

To a solution of bis(dibenzylideneacetone)palladium (0.015 g, 0.027mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene, 0.019 g,0.027 mmol) in tetrahydrofuran (8 mL) was added2-bromo-1-ethoxy-4-(2-ethoxypropan-2-yl)benzene (0.385 g, 1.341 mmol)from Example I-103C in 1 mL of tetrahydrofuran followed by a solution offreshly-prepared (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (5.96mL, 2.68 mmol). The reaction was stirred at ambient temperature for 3hours, another equivalent of Zn reagent (3 mL) was added and thereaction was stirred at ambient temperature for 16 hours. Anotherequivalent Zn reagent (3 mL) was added and the reaction was stirred atotal of 4 days at ambient temperature. The reaction was heated at 50°C. for 16 hours and heated at 70° C. for 3 hours. The reaction wascooled to ambient temperature and was diluted with ethyl acetate andsaturated aqueous ammonium chloride. The organic layer was separated,and washed with brine and concentrated. The residue was purified viachromatography on a 24 g silica gel cartridge, eluting with ethylacetate in heptanes at 0-100% gradient over a period of 12 minutes toprovide the crude product. The crude material was rechromatographed on a24 g silica gel cartridge, eluting with 100% dichloromethane for 7minutes followed by 100% ethyl acetate for 2 minutes to provide thetitle compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.25 (m, 1H), 7.24(d, J=0.8 Hz, 1H), 6.78 (m, 1H), 4.04 (q, J=6.9 Hz, 2H), 3.60 (s, 3H),3.18 (q, J=7.0 Hz, 2H), 1.59 (q, J=4.1 Hz, 2H), 1.51 (s, 6H), 1.36 (t,J=7.0 Hz, 3H), 1.13 (t, J=7.0 Hz, 3H), 1.10 (q, J=4.1 Hz, 2H). MS(APCI+) m/z 261 (M+H-CH₃CH₂OH)⁺.

Example I-103E1-(2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl)cyclopropanecarboxylic Acid

Methyl 1-(2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl)cyclopropanecarboxylate(0.295 g, 0.963 mmol) from Example I-103D was dissolved intetrahydrofuran (1.5 mL), methanol (1.500 mL), and water (1.500 mL). Themixture was treated with sodium hydroxide (0.193 g, 4.81 mmol, stirredat 35° C. for 16 hours, concentrated, cooled in an ice bath, andcarefully quenched with 1N aqueous citric acid (about 2.5 mL) until thepH ˜5. The resulting slurry was stirred vigorously and filtered. Theprecipitate was washed with water and dried in a vacuum oven overnightto provide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm10.48 (bs, 1H), 7.25 (m, 2H), 6.79 (d, J=9.1 Hz, 1H), 4.06 (q, J=6.9 Hz,2H), 3.17 (q, J=7.0 Hz, 2H), 1.65 (q, J=4.1 Hz, 2H), 1.49 (s, 6H), 1.38(t, J=6.9 Hz, 3H), 1.16 (q, J=4.1 Hz, 2H), 1.12 (t, J=7.0 Hz, 3H). MS(ESI−) m/z 291 (M−H)⁻.

Example I-103F1-[2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-ethoxy-5-(2-ethoxypropan-2-yl)phenyl)cyclopropanecarboxylic acid(50 mg, 0.171 mmol) from Example I-103E,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (65.6 mg, 0.342 mmol) and N,N-dimethylpyridin-4-amine(20.89 mg, 0.171 mmol) in anhydrous dichloromethane (1 mL) was added2-methylquinoline-5-sulfonamide (40 mg, 0.180 mmol). The reaction wasstirred at ambient temperature for 15 hours. The reaction was quenchedwith aqueous 2 N citric acid (0.2 mL) and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes to providethe crude material. The crude material was triturated with diethyl etherand filtered to provide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.38 (s, 1H), 8.79 (d, J=8.9 Hz, 1H), 8.18 (ddd,J=7.4, 5.2, 1.1 Hz, 2H), 7.83 (dd, J=8.4, 7.5 Hz, 1H), 7.53 (d, J=8.9Hz, 1H), 7.19 (dd, J=8.5, 2.3 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.74 (d,J=8.5 Hz, 1H), 3.63 (q, J=7.0 Hz, 2H), 3.09 (q, J=6.9 Hz, 2H), 2.67 (s,3H), 1.38 (s, 6H), 1.30 (q, J=4.4 Hz, 2H), 0.99 (t, J=6.9 Hz, 3H), 0.91(q, J=4.5 Hz, 2H), 0.72 (t, J=6.9 Hz, 3H). MS (ESI−) m/z 495 (M−H)⁻.

Example I-1041-[2-ethoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-104A 2-bromo-1-ethoxy-4-(2-methoxypropan-2-yl)benzene

To a solution of 2-(3-bromo-4-ethoxyphenyl)propan-2-ol (400 mg, 1.544mmol) Example I-103B in N,N-dimethylformamide (3 mL) at 0° C. was addedsodium hydride (123 mg, 3.09 mmol), 60% by weight in mineral oil. After30 minutes, iodomethane (0.193 mL, 3.09 mmol) was added and the reactionwas stirred at 20° C. for 6 hours. The mixture was quenched via additionof saturated aqueous ammonium chloride (70 mL) and extracted withdichloromethane. The crude material was purified by chromatography,eluting on 12 g silica gel cartridge with a gradient of 0-60% ethylacetate/heptanes over a period of 10 minutesto provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.57 (d, J=2.3 Hz, 1H),7.27 (d, J=8.5, 2.3 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 4.10 (q, J=7.0 Hz,2H), 3.05 (s, 3H), 1.49 (s, 6H), 1.47 (t, J=7.0 Hz, 3H). MS (DCI+) m/z241 (M+H-methanol)⁺.

Example I-104B Methyl1-(2-ethoxy-5-(2-methoxypropan-2-yl)phenyl)cyclopropanecarboxylate

To a solution of bis(dibenzylideneacetone)palladium (0.016 g, 0.028mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.020 g,0.028 mmol) in tetrahydrofuran (8 mL) at ambient temperature was added2-bromo-1-ethoxy-4-(2-methoxypropan-2-yl)benzene (0.3 85 g, 1.409 mmol)from Example I-104A in 1 mL tetrahydrofuran followed by a solution offreshly-prepared (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (6.26mL, 2.82 mmol). After 3 hours, additional Zn reagent (3 mL) was added,the reaction stirred at ambient temperature for 16 hours, additional Znreagent (3 mL) was added and the reaction was stirred a total of 4 daysat ambient temperature, and heated at 50° C. for 6 hours. The reactionmixture was cooled to ambient temperature and diluted with ethyl acetateand saturated aqueous ammonium chloride. The organic layer was washedwith brine and concentrated. The residue was purified via chromatographyon a 24 g silica gel cartridge, eluting with ethyl acetate in heptane at0-100% gradient over a period of 12 minutes to provide the titlecompound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.24 (dd, J=7.9, 2.4 Hz,1H), 7.23 (s, 1H), 6.79 (dd, J=7.9, 0.9 Hz, 1H), 4.05 (q, J=7.0 Hz, 2H),3.60 (s, 3H), 3.04 (s, 3H), 1.59 (q, J=4.1 Hz, 2H), 1.51 (s, 6H), 1.37(t, J=7.0 Hz, 3H), 1.11 (q, J=4.1 Hz, 2H). MS (ESI+) m/z 261(M+H-methanol)⁺.

Example I-104C1-(2-ethoxy-5-(2-methoxypropan-2-yl)phenyl)cyclopropanecarboxylic acid

Methyl1-(2-ethoxy-5-(2-methoxypropan-2-yl)phenyl)cyclopropanecarboxylate(0.345 g, 1.180 mmol) from Example I-104B was dissolved intetrahydrofuran (1.5 mL), methanol (1.500 mL), and water (1.500 mL), andtreated with sodium hydroxide (0.236 g, 5.90 mmol). The reaction mixturewas stirred at 35° C. for 16 hours, concentrated, cooled in an ice bath,and carefully quenched with 1N aqueous citric acid (about 3 mL) untilthe pH ˜5. The resulting slurry was stirred vigorously and the aqueouslayer was decanted off. The crude material was washed with water anddecanted. The material was washed with water and dried by azeotropingwith toluene (3×2 mL) to provide the title compound. ¹H NMR (501 MHz,chloroform-d) δ ppm 10.56 (bs, 1H), 7.24 (m, 2H), 6.80 (d, J=9.1 Hz,1H), 4.06 (q, J=7.0 Hz, 2H), 3.02 (s, 3H), 1.65 (q, J=4.1 Hz, 2H), 1.49(s, 6H), 1.39 (t, J=6.9 Hz, 3H), 1.17 (q, J=4.1 Hz, 2H). MS (ESI−) m/z277 (M−H)⁻.

Example I-104D1-[2-ethoxy-5-(2-methoxypropan-2-yl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-ethoxy-5-(2-methoxypropan-2-yl)phenyl)cyclopropanecarboxylic acid(50 mg, 0.180 mmol) from Example I-104C,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (68.9 mg, 0.359 mmol) and N,N-dimethylpyridin-4-amine(21.95 mg, 0.180 mmol) in anhydrous dichloromethane (1 mL) was added2-methylquinoline-5-sulfonamide (40 mg, 0.180 mmol). The reaction wasstirred at ambient temperature for 15 hours. The reaction was quenchedwith 0.2 mL of 2N aqueous citric acid and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes to providethe crude title compound. The crude material was triturated with diethylether and filtered to provide the title compound. ¹H NMR (501 MHz,dimethyl sulfoxide-d₆) δ ppm 11.40 (s, 1H), 8.80 (d, J=8.8 Hz, 1H),8.23-8.17 (m, 2H), 7.85 (dd, J=8.3, 7.5 Hz, 1H), 7.55 (d, J=8.9 Hz, 1H),7.20 (dd, J=8.5, 2.4 Hz, 1H), 7.05 (d, J=2.3 Hz, 1H), 6.76 (d, J=8.5 Hz,1H), 3.64 (q, J=6.9 Hz, 2H), 2.93 (s, 3H), 2.69 (s, 3H), 1.39 (s, 6H),1.31 (q, J=4.4 Hz, 2H), 0.93 (q, J=4.4 Hz, 2H), 0.74 (t, J=6.9 Hz, 3H).MS (ESI−) m/z 481 (M−H)⁻.

Example I-1051-[2-ethoxy-5-(1-methoxycyclobutyl)phenyl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-yl-carboxamide

To a solution of1-(2-ethoxy-5-(1-methoxycyclobutyl)phenyl)cyclopropanecarboxylic acid(55 mg, 0.189 mmol) from Example I-102E,N¹-((ethylimino)methylene)-N³-dimethylpropane-1,3-diamine hydrochloride(72.6 mg, 0.379 mmol) and N,N-dimethylpyridin-4-amine (23.14 mg, 0.189mmol) in anhydrous dichloromethane (1 mL) was added2-methylquinoline-5-sulfonamide (40 mg, 0.180 mmol). The reaction wasstirred at ambient temperature for 15 hours. The reaction mixture wasquenched with 0.2 mL of aqueous 2N citric acid and the residue waspurified via chromatography on a 12 g silica gel cartridge, eluting witha gradient of 0-10% methanol/dichloromethane over a period of 20 minutesto yield the product, which was triturated with diethyl ether andfiltered to provide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 11.43 (s, 1H), 8.79 (d, J=8.9 Hz, 1H), 8.23-8.14 (m,2H), 7.83 (t, J=7.9 Hz, 1H), 7.53 (d, J=8.9 Hz, 1H), 7.21 (dd, J=8.4,2.3 Hz, 1H), 7.04 (d, J=2.3 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.65 (q,J=7.0 Hz, 2H), 2.78 (s, 3H), 2.67 (s, 3H), 2.35-2.13 (m, 4H), 1.81 (dtd,J=15.6, 9.6, 4.7 Hz, 1H), 1.56 (dq, J=10.6, 8.2 Hz, 1H), 1.29 (q, J=4.4Hz, 2H), 0.92 (q, J=4.5 Hz, 2H), 0.74 (t, J=6.9 Hz, 3H). MS (ESI−) m/z493 (M−H)⁻.

Example I-1061-{5-methyl-2-[(oxetan-3-yl)oxy]phenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example I-93C (49.2 mg, 0.20 mmol, 1.1 eq) was weighed into a 4 mL vial.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HCl (68.4 mg, 0.36 mmol,2.0 eq) and 4-dimethylaminopyridine (24.2 mg, 0.20 mmol, 1.1 eq) indichloromethane (0.4 mL) was added to the vial containing the carboxylicacid. A slurry of 2-methylquinoline-5-sulfonamide in dichloromethane(0.8 mL) was added and the reaction was stirred overnight at ambienttemperature. The solvent was removed under a stream of nitrogen, and theresidue was dissolved in dimethyl sulfoxide/methanol. The mixture waspurified via preparative reverse phase HPLC/MS method trifluoroaceticacid 6 to provide the title compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.90 (dd, J=8.9, 0.9 Hz, 1H),8.29-8.21 (m, 2H), 7.91 (dd, J=8.5, 7.5 Hz, 1H), 7.63 (d, J=8.9 Hz, 1H),7.06-6.99 (m, 1H), 6.98 (d, J=2.3 Hz, 1H), 6.41 (d, J=8.2 Hz, 1H), 4.94(p, J=5.5 Hz, 1H), 4.61 (dd, J=7.2, 6.0 Hz, 2H), 4.12 (dd, J=7.2, 5.1Hz, 2H), 2.73 (s, 3H), 2.22 (s, 3H), 1.25 (q, J=4.3 Hz, 2H), 0.99 (q,J=4.4 Hz, 2H). MS (APCI) m/z 453.2 (M+H)⁺.

Example I-1071-(2-{[(2R)-1-methoxypropan-2-yl]oxy}-5-methylphenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Example I-107 was prepared as described in Example I-106, substitutingExample I-95C for Example I-93C. ¹H NMR (501 MHz, dimethylsulfoxide-d₆:D₂O=9:1 (v/v)) δ ppm 8.94 (d, J=8.9 Hz, 1H), 8.26 (d, J=7.9Hz, 2H), 7.92 (t, J=8.0 Hz, 1H), 7.66 (d, J=8.9 Hz, 1H), 7.08-7.02 (m,1H), 6.92 (d, J=2.3 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.36 (h, J=5.8 Hz,1H), 3.16 (s, 3H), 3.11-3.00 (m, 2H), 2.74 (s, 3H), 2.21 (s, 3H),1.37-1.30 (m, 1H), 1.23-1.15 (m, 1H), 1.07-0.99 (m, 1H), 0.93-0.84 (m,4H). MS (APCI) m/z 469.2 (M+H)⁺.

Example I-1081-[3-(dimethylamino)-6-(2-methylpropoxy)pyridin-2-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-108A 6-isobutoxy-N,N-dimethylpyridin-3-amine

5-Bromo-2-isobutoxypyridine (0.507 g, 2.203 mmol) [CAS #1251385-87-1]was combined with a 40% by weight solution of dimethylamine (3.65 g,32.4 mmol) in water and the mixture was degassed with a stream ofnitrogen for five minutes. 3 HPMC catalyst capsules (each containing 1.2mg allyl palladium, 4.5 mg cBRIDP(di-tert-butyl(2,2-diphenyl-1-methyl-1-cyclopropyl)phosphine), and 110mg potassium tert-butoxide) were added and the reaction was warmed to50° C. for 3 hours. The reaction was warmed at 50° C. for 24 hours, and40% aqueous dimethylamine (3.65 g, 32.4 mmol) and 2 more HPMC catalystcapsules were added. The mixture was heated at 50° C. for 16 hours. Thereaction was cooled and taken up in ethyl acetate and brine. Theorganics were separated and the solvent removed in vacuo. The residuewas purified using a 40 g silica gel cartridge with a gradient of 0-100%ethyl acetate/hexanes to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.67 (d, J=3.2 Hz, 1H), 7.16 (ddd, J=9.0, 3.2, 0.9Hz, 1H), 6.70-6.63 (m, 1H), 3.99 (dd, J=6.8, 1.1 Hz, 2H), 2.86 (d, J=0.8Hz, 6H), 2.07 (dtd, J=13.6, 6.8, 1.0 Hz, 1H), 1.01 (dd, J=6.7, 1.0 Hz,6H). MS (ESI+) m/z 195 (M+H)⁺.

Example I-108B 2-bromo-6-isobutoxy-N,N-dimethylpyridin-3-amine

6-Isobutoxy-N,N-dimethylpyridin-3-amine (0.152 g, 0.782 mmol) fromExample I-108A was combined with 1-bromopyrrolidine-2,5-dione (0.167 g,0.939 mmol) in acetonitrile (2 mL) and the reaction was stirred atambient temperature for 1 hour. The solvent was reduced in volume, andthe reaction was quenched with water (20 mL) and extracted with methyltert-butyl ether (100 mL). The organics were separated and the solventremoved in vacuo. The residue was purified using a 12 g silica gelcartridge with a gradient of 0-100% ethyl acetate/hexanes to provide thetitle compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.38 (d, J=8.5 Hz,1H), 6.68 (d, J=8.5 Hz, 1H), 4.03 (d, J=6.6 Hz, 2H), 2.74 (s, 6H), 2.07(dt, J=13.4, 6.7 Hz, 1H), 1.01 (d, J=6.7 Hz, 6H).

Example I-108C Methyl1-(3-(dimethylamino)-6-isobutoxypyridin-2-yl)cyclopropanecarboxylate

To a solution of 2-bromo-6-isobutoxy-N,N-dimethylpyridin-3-amine (62 mg,0.227 mmol) from Example I-108B in tetrahydrofuran (6 mL) was addedbis(dibenzylideneacetone)palladium (2.61 mg, 4.54 μmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (3.23 mg,4.54 mol). Nitrogen was bubbled through the solution for about 10minutes, and a 0.45 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (0.926 mL, 0.454 mmol)was added dropwise. The reaction was stirred for 16 hours at ambienttemperature. The reaction was quenched with saturated aqueous ammoniumchloride (1 mL) and the organics were separated and the crude materialwas purified via flash chromatography, eluting on a 12 g silica gelcartridge with 0-50% ethyl acetate/hexanes over 20 minutes to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.46 (dd,J=8.6, 0.6 Hz, 1H), 6.62 (dd, J=8.5, 0.6 Hz, 1H), 4.01 (dd, J=6.7, 0.6Hz, 2H), 3.66 (d, J=0.6 Hz, 3H), 2.58 (d, J=0.6 Hz, 6H), 2.05 (dp,J=13.4, 6.7 Hz, 1H), 1.49 (t, J=2.8 Hz, 2H), 1.45 (t, J=2.9 Hz, 2H),1.00 (dd, J=6.7, 0.6 Hz, 6H).

Example I-108D1-(3-(dimethylamino)-6-isobutoxypyridin-2-yl)cyclopropanecarboxylic Acid

To a solution of methyl1-(3-(dimethylamino)-6-isobutoxypyridin-2-yl)cyclopropanecarboxylate (53mg, 0.181 mmol) from Example I-108C in tetrahydrofuran (0.5 mL),methanol (0.5 mL) and water (0.5 mL) was added sodium hydroxide (43 mg,1.075 mmol). The reaction was warmed at 50° C. for 16 hours. The solventwas reduced under a stream of nitrogen and the reaction was quenchedwith 0.55 mL of 2 N aqueous citric acid. The aqueous layer was removedby pipette and the resulting material was washed with water (2×1 mL) anddried under vacuum to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.53 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 4.03(d, J=6.6 Hz, 2H), 2.80 (s, 6H), 2.06 (dp, J=13.4, 6.7 Hz, 1H), 1.72 (q,J=3.8, 3.3 Hz, 2H), 1.64-1.55 (m, 2H), 1.01 (d, J=6.7 Hz, 6H). MS(ESII+) m/z 279 (M+H)⁺.

Example I-108E1-[3-(dimethylamino)-6-(2-methylpropoxy)pyridin-2-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(3-(dimethylamino)-6-isobutoxypyridin-2-yl)cyclopropanecarboxylic acid(48 mg, 0.172 mmol) from Example I-108D,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (66.1 mg, 0.345 mmol) and N,N-dimethylpyridin-4-amine(21.07 mg, 0.172 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (35.9 mg, 0.172 mmol). The reaction was stirredat ambient temperature for 16 hours. The reaction was quenched with 0.2mL of 2 N aqueous citric acid and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes. The crudematerial was triturated with methanol and filtered to provide the titlecompound. ¹H NMR (400 MHz, dimethyl sulfoxide) δ ppm 12.06 (s, 1H),8.97-9.05 (m, 2H), 8.23-8.34 (m, 2H), 7.89 (dd, J=8.5, 7.4 Hz, 1H), 7.67(dd, J=8.6, 4.3 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H),3.88 (d, J=6.6 Hz, 2H), 2.28 (s, 6H), 1.94 (hept, J=6.7, 6.7 Hz, 1H),1.20 (q, J=4.1 Hz, 2H), 0.99 (q, J=3.9 Hz, 2H), 0.90 (d, J=6.7 Hz, 6H).MS (ESI−) m/z 467 (M−H)⁻.

Example I-1091-[5-(dimethylamino)-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-109A 3-bromo-2-isobutoxypyridine

3-Bromo-2-fluoropyridine (1.06 g, 6.02 mmol) and 2-methylpropan-1-ol(0.577 mL, 6.25 mmol) were combined and a 1M solution of potassium2-methylpropan-2-olate (7.23 mL, 7.23 mmol) in tetrahydrofuran wasadded, dropwise, and the temperature increased form 20-35° C. Thereaction was allowed to cool to ambient temperature and was stirred for1 hour. The mixture was quenched with water (50 mL) and extracted withmethyl tert-butyl ether (500 mL). The organics were washed with brine(50 mL), dried over sodium sulfate, filtered, and concentrated. Thecrude material was chromatographed using a 40 g silica gel cartridgewith a gradient of 5-100% ethyl acetate/hexanes to provide the titlecompound. H NMR (400 MHz, chloroform-d) δ ppm 8.08 (dd, J=4.9, 1.8 Hz,1H), 7.80 (dd, J=7.6, 1.7 Hz, 1H), 6.76 (dd, J=7.6, 4.9 Hz, 1H), 4.14(d, J=6.6 Hz, 2H), 2.15 (dp, J=13.4, 6.7 Hz, 1H), 1.06 (d, J=6.7 Hz,6H).

Example I-109B Methyl 1-(2-isobutoxypyridin-3-yl)cyclopropanecarboxylate

To a solution of 3-bromo-2-isobutoxypyridine (1.287 g, 5.59 mmol) fromExample I-109A in tetrahydrofuran (6 mL) was addedbis(dibenzylideneacetone)palladium (0.064 g, 0.112 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.080 g,0.112 mmol). Nitrogen was bubbled through the solution for about 10minutes. A 0.45 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (12 mL, 5.88 mmol) wasadded dropwise over 5 minutes and the temperature slowly increased from24.4-34.2° C. The reaction was stirred for 1 hour at ambienttemperature. Additional (1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide(5 mL, 2.45 mmol) was added and the reaction was stirred at ambienttemperature for 16 hours. The reaction was quenched with saturatedaqueous ammonium chloride (30 mL) and diluted with methyl tert-butylether (200 mL). The organics were washed with brine, dried over sodiumsulfate and filtered. The solvent was removed in vacuo and the crudematerial was purified via flash chromatography, eluting on a 40 g silicagel cartridge with 0-50% ethyl acetate/hexanes over 20 minutes toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.07(dd, J=5.1, 1.9 Hz, 1H), 7.44 (dd, J=7.2, 1.9 Hz, 1H), 6.82 (dd, J=7.2,5.1 Hz, 1H), 4.10 (d, J=6.3 Hz, 2H), 3.60 (s, 3H), 2.07 (dp, J=13.2, 6.6Hz, 1H), 1.67-1.57 (m, 2H), 1.13-1.07 (m, 2H), 1.01 (d, J=6.7 Hz, 6H).MS (APCI+) m/z 249.9 (M+H)⁺.

Example I-109C Methyl1-(5-bromo-2-isobutoxypyridin-3-yl)cyclopropanecarboxylate

Methyl 1-(2-isobutoxypyridin-3-yl)cyclopropanecarboxylate (1.17 g, 4.69mmol) from Example I-109B was combined with 1-bromopyrrolidine-2,5-dione(0.971 g, 5.46 mmol) in N,N-dimethylformamide (10 mL). The reaction wasstirred at 50° C. for 19 hours. The reaction was cooled, quenched withwater (30 mL) and extracted with methyl tert-butyl ether (200 mL). Theorganics were separated, washed with water and brine, dried over sodiumsulfate, and filtered. The solvent removed in vacuo. The residue waspurified using a 40 g silica gel cartridge with a gradient of 0-50%ethyl acetate/hexanes over 40 minutes to provide the title compound. ¹HNMR (400 MHz, chloroform-d) δ ppm 8.10 (d, J=2.4 Hz, 1H), 7.53 (d, J=2.4Hz, 1H), 4.07 (d, J=6.3 Hz, 2H), 3.61 (s, 3H), 2.06 (dp, J=13.2, 6.6 Hz,1H), 1.64 (q, J=4.3 Hz, 2H), 1.10 (q, J=4.3 Hz, 2H), 1.00 (d, J=6.7 Hz,6H). MS (APCI+) m/z 330 (Br doublet) (M+H)⁺.

Example I-109D Methyl1-(5-(dimethylamino)-2-isobutoxypyridin-3-yl)cyclopropanecarboxylate

Methyl 1-(5-bromo-2-isobutoxypyridin-3-yl)cyclopropanecarboxylate (0.449g, 1.368 mmol) from Example I-109C was combined with potassium phosphate(0.926 g, 4.36 mmol), and DAVEPHOS-PD-G3 (methanesulfonato2-dicyclohexylphosphino-2-(N,N-dimethylamino)biphenyl(2′-amino-1,1′-biphenyl-2-yl)palladium(II), 0.104 g, 0.137 mmol) and put under nitrogen.Dimethylamine (6 mL, 12.00 mmol) 2M in tetrahydrofuran was added and themixture was degassed with a stream of nitrogen for 3 minutes. Thereaction was sealed and warmed to 80° C. for 72 hours. The reaction wascooled and the solvent was reduced under a stream of nitrogen. Theorganics were filtered and purified using a 40 g silica gel cartridgewith a gradient of 0-100% ethyl acetate/hexanes to provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.58 (d, J=3.0 Hz, 1H),7.06 (d, J=3.0 Hz, 1H), 4.02 (d, J=6.4 Hz, 2H), 3.61 (s, 3H), 2.87 (s,6H), 2.04 (dp, J=13.2, 6.6 Hz, 1H), 1.62 (q, J=4.2 Hz, 2H), 1.11 (q,J=4.2 Hz, 2H), 1.00 (d, J=6.7 Hz, 6H). MS (ESI+) m/z 293 (M+H)⁺.

Example I-109E1-(5-(dimethylamino)-2-isobutoxypyridin-3-yl)cyclopropanecarboxylic Acid

To a solution of methyl1-(5-(dimethylamino)-2-isobutoxypyridin-3-yl)cyclopropanecarboxylate(350 mg, 1.197 mmol) from Example I-109D in tetrahydrofuran (3 mL),methanol (3 mL) and water (3 mL) was added sodium hydroxide (403 mg,10.08 mmol). The reaction was warmed at 50° C. for 2 hours. The solventwas reduced under a stream of nitrogen and the reaction was quenchedwith 4.3 of 2N aqueous citric acid. The aqueous layer was removed bypipette and the resulting material was washed with water (2×1 mL) andazeotroped with toluene to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.59 (d, J=3.0 Hz, 1H), 7.06 (d, J=3.1 Hz, 1H), 4.02(d, J=6.4 Hz, 2H), 2.85 (s, 6H), 2.05 (dp, J=13.2, 6.6 Hz, 1H), 1.63 (q,J=4.1 Hz, 2H), 1.14 (q, J=4.2 Hz, 2H), 1.00 (d, J=6.7 Hz, 6H). MS (ESI+)m/z 279 (M+H)⁺.

Example I-109F1-[5-(dimethylamino)-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(5-(dimethylamino)-2-isobutoxypyridin-3-yl)cyclopropanecarboxylic acid(58 mg, 0.208 mmol) from Example I-109E,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (80 mg, 0.417 mmol) and N,N-dimethylpyridin-4-amine (25.5mg, 0.208 mmol) in anhydrous dichloromethane (1 mL) was added2-methylquinoline-5-sulfonamide (49 mg, 0.220 mmol). The reaction wasstirred at ambient temperature overnight. The reaction was quenched with0.2 mL of 2N aqueous citric acid and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes. Thematerial was further purified by reverse-phase preparative HPLC on aPhenomenex® Luna® C8(2) 5 μm 100A AXIA™ column (30 mm×150 mm). Agradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B)was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0minutes linear gradient 95-10% A) to provide the title compound as atrifluoroacetic acid salt. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm11.57 (s, 1H), 8.82 (d, J=8.9 Hz, 1H), 8.26-8.18 (m, 2H), 7.87 (t, J=8.0Hz, 1H), 7.80 (d, J=2.9 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.40 (d, J=2.9Hz, 1H), 3.54 (d, J=6.5 Hz, 2H), 2.94 (s, 6H), 2.70 (s, 3H), 1.33 (q,J=4.4 Hz, 2H), 1.22 (dp, J=13.3, 6.7 Hz, 1H), 1.01 (q, J=4.5 Hz, 2H),0.55 (d, J=6.7 Hz, 6H). MS (APCI+) m/z 483 (M+H)⁺.

Example I-1101-[2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-110A Methyl 2-(3-bromo-4-methoxyphenyl)-2-methylpropanoate

A solution of methyl 2-(4-methoxyphenyl)-2-methylpropanoate (2 g, 9.60mmol) [CAS #6274-50-6] and N-bromosuccinimide (1.880 g, 10.56 mmol) inacetonitrile (12.00 mL) was stirred at 38° C. for 16 hours. The solventevaporated in vacuo. The crude material was trituated withdichloromethane, and filtered. The filtrate was purified bychromatography, eluting on 24 g silica gel cartridge with a gradient of0-50% ethyl acetate/heptanes over a period of 12 minutes to provide thetitle compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.52 (d, J=2.4 Hz,1H), 7.24 (dd, J=8.6, 2.4 Hz, 1H), 6.85 (d, J=8.7 Hz, 1H), 3.88 (s, 3H),3.65 (s, 3H), 1.55 (s, 6H). MS (APCI+) m/z 287 (M+H)⁺.

Example I-110B 2-(3-bromo-4-methoxyphenyl)-2-methylpropan-1-ol

To a solution of methyl 2-(3-bromo-4-methoxyphenyl)-2-methylpropanoate(2.1 g, 7.31 mmol) from Example I-110A in dichloromethane (20 mL) at 0°C. was added a solution of 1M diisobutylaluminium hydride indichloromethane (14.63 mL, 14.63 mmol). The reaction was stirred at 0°C. for 2 hours and quenched with 30 mL 1 N aqueous citric acid. Theorganic layer was separated and the solvent was evaporated in vacuo. Theresulting residue was chromatographed using a 24 g silica gel cartridgewith gradient of 0-100% ethyl acetate/heptanes over a period of 10minutes to provide the title compound. ¹H NMR (500 MHz, chloroform-d) δppm 7.55 (d, J=2.4 Hz, 1H), 7.28 (dd, J=8.6, 2.4 Hz, 1H), 6.87 (d, J=8.6Hz, 1H), 3.88 (s, 3H), 3.58 (d, J=6.3 Hz, 2H), 1.30 (s, 6H), 1.22 (t,J=6.5 Hz, 1H). MS (ESI+) m/z 241 (M+H-H₂O)⁺.

Example I-110C2-bromo-1-methoxy-4-(1-methoxy-2-methylpropan-2-yl)benzene

To a solution of 2-(3-bromo-4-methoxyphenyl)-2-methylpropan-1-ol (700mg, 2.70 mmol) from Example I-110B in N,N-dimethylformamide (5 mL) at 0°C. was added sodium hydride (216 mg, 5.40 mmol) as a 60% by weightdispersion in mineral oil. After 30 minutes, iodomethane (0.338 mL, 5.40mmol) was added and the reaction was stirred 1 hour at 0° C. and for 2hours at ambient temperature. The mixture was quenched via addition ofsaturated aqueous ammonium chloride (80 mL) and extracted with ethylacetate. The crude material was purified by chromatography, eluting on12 g silica gel cartridge with a gradient of 0-50% ethylacetate/heptanes over a period of 10 minutes to provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.53 (d, J=2.4 Hz, 1H),7.30-7.26 (d, J=8.6, 2.4 Hz, 2H), 6.84 (d, J=8.6 Hz, 1H), 3.87 (s, 3H),3.34 (s, 2H), 3.31 (s, 3H), 1.29 (s, 6H). MS (APCI+) m/z 241(M+H-methanol)⁺.

Example I-110D Methyl1-(2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropanecarboxylate

To a solution of2-bromo-1-methoxy-4-(1-methoxy-2-methylpropan-2-yl)benzene (0.665 g,2.434 mmol) from Example I-110C in tetrahydrofuran (8 mL) was addedbis(dibenzylideneacetone)palladium (0.028 g, 0.049 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.035 g,0.049 mmol). Nitrogen was bubbled through the solution for about 3minutes, and a 0.49 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (9.94 mL, 4.87 mmol)was added dropwise over 5 minutes. The reaction was stirred for 30minutes at ambient temperature and for 3 hours at 67° C. The reactionwas cooled to ambient temperature, quenched with saturated aqueousammonium chloride (40 mL), diluted with ethyl acetate (40 mL), and thelayers were separated. The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo. The crude material was purified viachromatography on a 24 g silica gel cartridge, eluting with 100%dichloromethane for 13 minutes to provide the title compound. ¹H NMR(501 MHz, chloroform-d) δ ppm 7.25 (dd, J=8.6, 2.5 Hz, 1H), 7.20 (d,J=2.5 Hz, 1H), 6.80 (d, J=8.6 Hz, 1H), 3.80 (s, 3H), 3.60 (s, 3H), 3.35(s, 2H), 3.31 (s, 3H), 1.59 (q, J=4.0 Hz, 2H), 1.30 (s, 6H), 1.11 (q,J=4.1 Hz, 2H). MS (APCI+) m/z 261 (M+H-methanol)⁺.

Example I-110E1-(2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropanecarboxylicAcid

Methyl1-(2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropanecarboxylate(0.4 g, 1.368 mmol) from Example I-110D was dissolved in tetrahydrofuran(1.8 mL) and methanol (1.8 mL), and water (1.8 mL) and treated withsodium hydroxide (0.274 g, 6.84 mmol). The reaction mixture was stirredat 35° C. overnight, concentrated, cooled in an ice bath and carefullyquenched with 1N aqueous citric acid (about 3.4 mL) until the pH ˜5. Theresulting slurry was stirred vigorously and the aqueous layer wasdecanted. The crude material was dissolved in ether. The mixture wasconcentrated, azeotroped with toluene (3×10 mL) to provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.25 (d, J=8.5, 2.5 Hz,1H), 7.20 (d, J=2.5 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 3.82 (s, 3H), 3.33(s, 2H), 3.29 (s, 3H), 1.64 (q, J=4.0 Hz, 2H), 1.29 (s, 6H), 1.17 (q,J=4.1 Hz, 2H). MS (ESI−) m/z 277 (M−H)⁻.

Example I-110F1-[2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl)cyclopropanecarboxylicacid (60 mg, 0.216 mmol) from Example I-110E,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (83 mg, 0.431 mmol) and N,N-dimethylpyridin-4-amine (29.0mg, 0.237 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (44.9 mg, 0.216 mmol). After 16 hours, thereaction was quenched with 1 mL of 1N aqueous citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. Thematerial was triturated with diethyl ether (1.5 mL) and filtered toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.50 (s, 1H), 9.06 (dd, J=4.1, 1.6 Hz, 1H), 8.99 (d, J=8.7 Hz, OH),8.35 (d, J=8.4 Hz, 1H), 8.31 (dd, J=7.5, 1.3 Hz, 1H), 7.94 (dd, J=8.4,7.5 Hz, 1H), 7.72 (dd, J=8.8, 4.2 Hz, 1H), 7.23 (dd, J=8.6, 2.5 Hz, 1H),7.07 (d, J=2.5 Hz, 1H), 6.77 (d, J=8.6 Hz, 1H), 3.33 (s, 3H), 3.30 (s,2H), 3.21 (s, 3H), 1.30 (q, J=4.4 Hz, 2H), 1.22 (s, 6H), 0.96 (q, J=4.4Hz, 2H). MS (ESI+) m/z 469 (M+H)⁺.

Example I-1111-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-111A 2-bromo-4-ethylphenol

To a cooled 0° C. solution of of 4-ethylphenol (12.94 g, 106 mmol) indichloromethane (212 mL) was added dibromine (5.70 mL, 111 mmol) slowly.After the addition was complete, the reaction mixture was stirred for 5minutes and quenched with 1N aqueous NaOH. The reaction mixture wasdiluted with water and the organic layer was separated, concentrated andpurified on a 220 g silica gel cartridge eluting with a gradient 0-20%methyl tert-butyl ether/heptanes to provide the title compound. ¹H NMR(400 MHz, chloroform-d) δ ppm 7.28 (d, J=2.1 Hz, 1H), 7.03 (dd, J=8.3,2.1 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 5.34 (s, 1H), 2.56 (q, J=7.6 Hz,2H), 1.32-1.15 (t, 3H).

Example I-111B (R)-2-bromo-4-ethyl-1-((1-methoxypropan-2-yl)oxy)benzene

Into a 100 mL flask was added 2-bromo-4-ethylphenol (0.669 g, 3.33 mmol)from Example I-111A and triphenylphosphine (1.397 g, 5.33 mmol) intetrahydrofuran (16 mL). The mixture was stirred briefly at ambienttemperature under nitrogen, and (E)-diisopropyldiazene-1,2-dicarboxylate (1.049 mL, 5.33 mmol) was added. The mixturewas stirred briefly under nitrogen at ambient temperature,(S)-1-methoxypropan-2-ol (0.326 mL, 3.33 mmol) was added dropwise andthe reaction was stirred overnight at ambient temperature. The solventwas removed under reduced pressure, and the crude material was purifiedby chromatography, eluting on a 24 g silica gel cartridge with agradient of 0-30% ethyl acetate/heptanes over a period of 10 minutes toprovide the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.36(d, J=2.2 Hz, 1H), 7.05 (dd, J=8.3, 2.2 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H),4.55-4.36 (m, 1H), 3.63 (dd, J=10.3, 5.8 Hz, 1H), 3.51 (dd, J=10.3, 4.7Hz, 1H), 3.43 (s, 3H), 2.57 (q, J=7.6 Hz, 2H), 1.34 (d, J=6.2 Hz, 3H),1.20 (t, J=7.6 Hz, 3H). MS (APCI+) m/z 273 (M+H)⁺.

Example I-111C (R)-methyl1-(5-ethyl-2-((1-methoxypropan-2-yl)oxy)phenyl)cyclopropanecarboxylate

To a solution of(R)-2-bromo-4-ethyl-1-((1-methoxypropan-2-yl)oxy)benzene (0.48 g, 1.757mmol) from Example I-111B in tetrahydrofuran (7 mL) was addedbis(dibenzylideneacetone)palladium (0.020 g, 0.035 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.025 g,0.035 mmol). Nitrogen was bubbled through the solution for about 3minutes, then a 0.54 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (7.81 mL, 3.51 mmol)was added dropwise over 5 minutes. The reaction was stirred for 16 hoursat 35° C. The reaction mixture was quenched with saturated aqueousammonium chloride (40 mL), diluted with ethyl acetate (40 mL), and thelayers were separated. The organic layer was dried over sodium sulfate,filtered and concentrated in vacuo. The crude material was purified viachromatography on a 24 g silica gel cartridge, eluting with ethylacetate in heptane at 0-100% gradient over a period of 12 minutes. Thematerial was chromatographed again on a 12 g silica gel cartridge,eluting with 100% dichloromethane for 8 mins to provide the titlecompound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.05 (dd, J=8.3, 2.3 Hz,1H), 7.01 (d, J=2.3 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 4.53 (h, J=5.9 Hz,1H), 3.59 (s, 3H), 3.57 (dd, J=10.2, 5.7 Hz, 1H), 3.42 (dd, J=10.1, 5.1Hz, 1H), 3.39 (s, 3H), 2.58 (q, J=7.6 Hz, 2H), 1.58-1.55 (m, 2H), 1.27(d, J=6.2 Hz, 3H), 1.21 (t, J=7.6 Hz, 3H), 1.11 (t, J=3.8 Hz, 2H). MS(APCI+) m/z 293 (M+H)⁺.

Example I-111D(R)-1-(5-ethyl-2-((1-methoxypropan-2-yl)oxy)phenyl)cyclopropanecarboxylicAcid

(R)-Methyl1-(5-ethyl-2-((1-methoxypropan-2-yl)oxy)phenyl)cyclopropanecarboxylate(0.44 g, 1.505 mmol) from Example I-111C was dissolved intetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), and treatedwith sodium hydroxide (0.301 g, 7.52 mmol). The reaction mixture wasstirred at 35° C. overnight, concentrated, cooled in an ice bath, andcarefully quenched with 1N aqueous citric acid (about 3.6 mL) until thepH ˜5. The resulting slurry was extracted with dichloromethane, andconcentrated. The crude material was azeotroped with toluene (3×10 mL)to provide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm7.09-7.02 (m, 2H), 6.82 (d, J=8.1 Hz, 1H), 4.55 (h, J=6.0 Hz, 1H), 3.58(dd, J=10.2, 5.6 Hz, 1H), 3.44 (dd, J=10.2, 5.0 Hz, 1H), 3.38 (s, 3H),2.56 (q, J=7.6 Hz, 2H), 1.66-1.56 (m, 2H), 1.30 (d, J=6.2 Hz, 3H), 1.19(t, J=7.6 Hz, 3H), 1.17-1.11 (m, 2H). MS (ESI−) m/z 279 (M+H)⁺.

Example I-111E1-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(R)-1-(5-ethyl-2-((1-methoxypropan-2-yl)oxy)phenyl)cyclopropanecarboxylicacid (60 mg, 0.216 mmol) from Example I-111D,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (83 mg, 0.431 mmol) and N,N-dimethylpyridin-4-amine (29.0mg, 0.237 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (44.9 mg, 0.216 mmol). After 16 hours, thereaction was quenched with 1 mL of 1N aqueous citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. The crudematerial was triturated with diethyl ether (1.5 mL) and filtered toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.46 (s, 1H), 9.10-8.98 (m, 2H), 8.43-8.24 (m, 2H), 7.92 (t, J=7.9Hz, 1H), 7.71 (dd, J=8.7, 4.3 Hz, 1H), 7.04 (dd, J=8.4, 2.2 Hz, 1H),6.93 (d, J=2.3 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.35 (p, J=5.9 Hz, 1H),3.15 (s, 3H), 3.06 (dd, J=10.3, 5.6 Hz, 1H), 2.99 (dd, J=10.3, 5.1 Hz,1H), 2.51 (q, J=7.6 Hz, 2H), 1.36 (ddd, J=10.8, 6.8, 4.3 Hz, 1H), 1.22(ddd, J=9.5, 6.8, 4.3 Hz, 1H), 1.14 (t, J=7.6 Hz, 3H), 1.02 (bs, 1H),0.88 (bs, 1H), 0.83 (d, J=6.2 Hz, 3H). MS (APCI+) m/z 469 (M+H)⁺.

Example I-1121-(5-ethyl-2-{[(2R)-1-methoxypropan-2-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(R)-1-(5-ethyl-2-((1-methoxypropan-2-yl)oxy)phenyl)cyclopropanecarboxylicacid (60 mg, 0.216 mmol) from Example I-111D,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (83 mg, 0.431 mmol) and N,N-dimethylpyridin-4-amine (29.0mg, 0.237 mmol) in anhydrous dichloromethane (1 mL) was added2-methylquinoline-5-sulfonamide (47.9 mg, 0.216 mmol). After 16 hours,the reaction was quenched with 1 mL of 1N aqueous citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. The crudematerial was triturated with diethyl ether (0.5 mL) and filtered toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.40 (s, 1H), 8.90 (d, J=8.9 Hz, 1H), 8.21 (dd, J=7.8, 4.6 Hz, 2H),7.85 (t, J=8.0 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.04 (dd, J=8.4, 2.2 Hz,1H), 6.93 (d, J=2.3 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 4.36 (p, J=5.9 Hz,1H), 3.15 (s, 3H), 3.06 (dd, J=10.3, 5.6 Hz, 1H), 3.00 (dd, J=10.3, 5.1Hz, 1H), 2.70 (s, 3H), 2.50 (q, J=7.6 Hz, 2H), 1.36 (ddd, J=11.1, 6.7,4.4 Hz, 1H), 1.22 (ddd, J=9.6, 7.0, 4.3 Hz, 1H), 1.14 (t, J=7.6 Hz, 3H),1.02 (bs, 1H), 0.88 (bs, 1H), 0.85 (d, J=6.2 Hz, 3H). MS (APCI+) m/z 483(M+H)⁺.

Example I-1131-{2-[(2S)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-113A (S)-2-bromo-1-(2-methoxypropoxy)-4-methylbenzene

To a cooled (−30° C.) solution of (2S)-2-methoxy-1-propanol (0.637 mL,6.13 mmol) in dichloromethane (6 mL) was added methanesulfonyl chloride(0.717 mL, 9.20 mmol) followed by dropwise addition ofN-ethyl-N-isopropylpropan-2-amine (1.713 mL, 9.81 mmol). The mixture wasstirred at −20° C. for 45 minutes, quenched with cold 1N aqueous HCl andbrine and diluted with dichloromethane. The organics were separated,dried over sodium sulfate, filtered, and concentrated to provide thecrude mesylate. The crude mesylate was combined with2-bromo-4-methylphenol (0.5 mL, 4.09 mmol) and cesium carbonate (4.00 g,12.26 mmol) in anhydrous N,N-dimethylformamide and the reaction washeated at 50° C. for 16 hours. The reaction was cooled to ambienttemperature, diluted with water (40 mL) and ethyl acetate (200 mL), andthe layers were separated. The organics were washed with water andbrine, dried over anhydrous sodium sulfate, filtered through silica gel,and concentrated. The residue was purified via chromatography on a 40 gsilica gel cartridge, eluting with ethyl acetate in hexanes at 0-40%gradient over 20 minutes. The material was chromatographed again using a40 g silica gel cartridge with a gradient of 0-50% methyl tert-butylether/hexanes over 40 minutes to provide the title compound. ¹H NMR (400MHz, chloroform-d) δ ppm 7.37 (d, J=2.2 Hz, 1H), 7.04 (dq, J=8.3, 0.9Hz, 1H), 6.80 (d, J=8.2 Hz, 1H), 4.03 (dd, J=9.5, 5.9 Hz, 1H), 3.89 (dd,J=9.5, 4.8 Hz, 1H), 3.82-3.74 (m, 1H), 3.50 (d, J=0.5 Hz, 3H), 2.31-2.23(m, 3H), 1.31 (d, J=6.3 Hz, 3H). MS (ESI+) m/z 259 (M+H)⁺ brominedoublet.

Example I-113B (S)-methyl1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylate

To a solution of (S)-2-bromo-1-(2-methoxypropoxy)-4-methylbenzene (0.545g, 2.103 mmol) from Example I-113A in tetrahydrofuran (4 mL) was addedbis(dibenzylideneacetone)palladium (0.024 g, 0.042 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.030 g,0.042 mmol). Nitrogen was bubbled through the solution for about 3minutes, and a 0.45 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (9.35 mL, 4.21 mmol)was added dropwise over 5 minutes. The reaction mixture was stirred atambient temperature for 15 hours. The reaction was quenched withsaturated aqueous ammonium chloride (20 mL) and diluted with ethylacetate (200 mL). Pyrrolidine-1-carbodithioic acid, ammonia salt (6.91mg, 0.042 mmol) was added to sequester the Pd and the mixture wasstirred for 30 minutes. Decolorizing charcoal was added and the layerswere filtered and separated. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo. The residue was purifiedvia flash chromatography, eluting on a 40 g silica gel cartridge with0-50% ethyl acetate/hexanes over 20 minutes to provide the titlecompound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.06 (ddd, J=8.2, 2.3,0.9 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.77 (d, J=8.2 Hz, 1H), 4.03 (dd,J=9.3, 5.6 Hz, 1H), 3.83 (dd, J=9.3, 5.3 Hz, 1H), 3.70 (dtd, J=11.7,6.3, 5.4 Hz, 1H), 3.62 (s, 3H), 3.46 (s, 3H), 2.30 (d, J=0.7 Hz, 3H),1.65-1.59 (m, 2H), 1.27 (d, J=6.3 Hz, 3H), 1.17-1.11 (m, 2H). MS (ESI+)m/z 279 (M+H)⁺.

Example I-113C(S)-1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylic Acid

(S)-Methyl1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylate (0.574 g,2.062 mmol) from Example I-113B was dissolved in tetrahydrofuran (2 mL),methanol (2 mL) and water (2 mL). The mixture was treated with sodiumhydroxide (0.577 g, 14.44 mmol) and stirred at 70° C. for 45 minutes.The reaction mixture was reduced in volume, cooled in an ice bath andcarefully quenched with 3N aqueous HCl (about 5 mL, diluted with ice)until the pH was acidic. The resulting material was stirred vigorouslyand the water was decanted. The material was washed with water and driedunder a stream of nitrogen to provide the title compound. ¹H NMR (400MHz, chloroform-d) δ ppm 7.08-6.96 (m, 2H), 6.75 (d, J=8.2 Hz, 1H), 4.01(dd, J=9.3, 5.7 Hz, 1H), 3.83 (dd, J=9.4, 5.1 Hz, 1H), 3.70 (hept,J=6.0, 5.6 Hz, 1H), 3.44 (s, 3H), 2.27 (s, 3H), 1.63 (q, J=2.9 Hz, 2H),1.26 (d, J=6.3 Hz, 3H), 1.21-1.11 (m, 2H). MS (ESI−) m/z 263 (M−H)⁻.X-ray analysis to confirmed absolute stereochemistry (S).

Example I-113D1-{2-[(2S)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(S)-1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylic acid(62 mg, 0.235 mmol) from Example I-113C,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (90 mg, 0.469 mmol) and N,N-dimethylpyridin-4-amine (28.7mg, 0.235 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (59 mg, 0.283 mmol). The reaction was stirred atambient temperature for 15 hours. The reaction was quenched with 0.2 mLof aqueous 2N citric acid and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes. Thematerial was dissolved in methanol/dimethyl sulfoxide and purified byreverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 ÅAXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound as a trifluoroacetic acid salt. ¹H NMR(400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.45 (s, 1H), 9.02 (dd, J=4.2,1.6 Hz, 1H), 8.92-8.88 (m, 1H), 8.34-8.27 (m, 2H), 7.90 (dd, J=8.4, 7.5Hz, 1H), 7.65 (dd, J=8.8, 4.2 Hz, 1H), 7.01 (dd, J=8.3, 2.1 Hz, 1H),6.93 (d, J=2.2 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 3.56 (dd, J=9.6, 5.9 Hz,1H), 3.31 (dd, J=9.5, 5.2 Hz, 1H), 3.05 (s, 3H), 2.89-2.75 (m, 1H), 2.19(s, 3H), 1.23 (tq, J=9.4, 3.4 Hz, 2H), 1.00-0.92 (m, 1H), 0.88 (ddd,J=7.9, 5.6, 2.7 Hz, 1H), 0.75 (d, J=6.3 Hz, 3H). MS (ESI+) m/z 455(M+H)⁺.

Example I-1141-{2-[(2S)-2-methoxypropoxy]-5-methylphenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(S)-1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylic acid(62 mg, 0.235 mmol) from Example I-113C,Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (90 mg, 0.469 mmol) and N,N-dimethylpyridin-4-amine (28.7mg, 0.235 mmol) in anhydrous dichloromethane (1 mL) was added2-methylquinoline-5-sulfonamide (53 mg, 0.238 mmol). The reaction wasstirred at ambient temperature for 16 hours. The reaction was quenchedwith 0.2 mL of 2N aqueous citric acid and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes. The crudematerial was dissolved in methanol/dimethyl sulfoxide and was purifiedby reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound as a trifluoroacetic acid salt. ¹H NMR(400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.43 (s, 1H), 8.90 (d, J=8.9 Hz,1H), 8.24 (d, J=7.7 Hz, 2H), 7.89 (t, J=8.0 Hz, 1H), 7.63 (d, J=9.0 Hz,1H), 7.06-6.97 (m, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.72 (d, J=8.2 Hz, 1H),3.60 (dd, J=9.5, 6.0 Hz, 1H), 3.37 (dd, J=9.6, 5.2 Hz, 1H), 3.06 (s,3H), 2.90 (h, J=6.2 Hz, 1H), 2.72 (s, 3H), 2.19 (s, 3H), 1.30-1.15 (m,2H), 0.95 (ddd, J=9.1, 5.3, 2.5 Hz, 1H), 0.89 (ddd, J=8.0, 5.4, 2.2 Hz,1H), 0.79 (d, J=6.3 Hz, 3H). MS (ESI+) m/z 469 (M+H)⁺.

Example I-1151-{2-[(2R)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-115A (R)-2-bromo-1-(2-methoxypropoxy)-4-methylbenzene

To a cooled (−30° C.) solution of (R)-2-methoxypropan-1-ol (0.553 g,6.13 mmol) in dichloromethane (6 mL) was added methanesulfonyl chloride(0.717 mL, 9.20 mmol) followed by dropwise addition ofN-ethyl-N-isopropylpropan-2-amine (1.713 mL, 9.81 mmol). The mixture wasstirred at −20° C. for 45 minutes, quenched with cold 1N aqueous HCl andbrine, and diluted with dichloromethane. The organics were separated anddried over sodium sulfate and the solvent removed in vacuo to give crudemesylate. The crude mesylate was combined with 2-bromo-4-methylphenol(0.5 mL, 4.09 mmol) and cesium carbonate (4.08 g, 12.52 mmol) inanhydrous N,N-dimethylformamide and the reaction was heated at 70° C.for 15 hours. The reaction was diluted with ethyl acetate and filtered.The material was washed with 200 mL of ethyl acetate. The organics weresequentially washed with 1N aqueous sodium hydroxide (40 mL), water (40mL) and brine (40 mL). The organics were dried over anhydrous sodiumsulfate, filtered, and concentrated. The residue was purified viachromatography on a 80 g silica gel cartridge, eluting with 0-50% methyltert-butyl ether/hexanes over 40 minutes to provide the title compound.¹H NMR (501 MHz, chloroform-d) δ ppm 7.38 (dd, J=2.2, 0.8 Hz, 1H), 7.06(ddt, J=8.3, 2.2, 0.7 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H), 4.04 (dd, J=9.5,5.9 Hz, 1H), 3.90 (dd, J=9.5, 4.8 Hz, 1H), 3.79 (pd, J=6.2, 4.9 Hz, 1H),3.52 (d, J=0.6 Hz, 3H), 2.29 (d, J=0.8 Hz, 3H), 1.35-1.29 (m, 3H).

Example I-115B (R)-methyl1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylate

To a solution of (R)-2-bromo-1-(2-methoxypropoxy)-4-methylbenzene (0.595g, 2.296 mmol) from Example I-115A in tetrahydrofuran (4 mL) was addedbis(dibenzylideneacetone)palladium (0.026 g, 0.046 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.033 g,0.046 mmol). Nitrogen was bubbled through the solution for about 3minutes. A tetrahydrofuran solution (0.45M) of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (10.20 mL, 4.59 mmol)was added dropwise over 5 minutes. The reaction was stirred at ambienttemperature for 15 hours. The reaction was quenched with saturatedaqueous ammonium chloride (20 mL) and diluted with methyl tert-butylether (200 mL). The layers were separated. The organic layer was driedover sodium sulfate, filtered and concentrated in vacuo. The crudematerial was purified via flash chromatography, eluting on a 40 g silicagel cartridge with 0-100% methyl tert-butyl ether/hexanes over 40minutes to provide the title compound. ¹H NMR (400 MHz, chloroform-d) δppm 7.07-7.00 (m, 2H), 6.75 (d, J=8.2 Hz, 1H), 4.01 (dd, J=9.3, 5.6 Hz,1H), 3.82 (dd, J=9.3, 5.3 Hz, 1H), 3.72-3.64 (m, 1H), 3.61 (s, 3H), 3.45(s, 3H), 2.29 (s, 3H), 1.60 (q, J=3.2 Hz, 2H), 1.26 (d, J=6.3 Hz, 3H),1.13 (dt, J=4.2, 2.5 Hz, 2H). MS (ESI+) m/z 279 (M+H)⁺.

Example I-115C(R)-1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylic Acid

(R)-Methyl1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylate (0.634 g,2.278 mmol) from Example I-115B was dissolved in tetrahydrofuran (2 mL),methanol (2 mL), and water (2 mL), treated with sodium hydroxide (0.787g, 19.68 mmol), and stirred at 50° C. After 2 hours, the reactionmixture was reduced in volume, cooled in an ice bath and carefullyquenched with 3N aqueous HCl (about 7 mL, diluted with ice) until the pHwas acidic. The resulting material was stirred vigorously and the waterwas decanted. The material was washed with water and dried under astream of nitrogen to provide the title compound. ¹H NMR (501 MHz,chloroform-d) δ ppm 7.08-7.01 (m, 2H), 6.76 (d, J=8.2 Hz, 1H), 4.04 (dd,J=9.3, 5.6 Hz, 1H), 3.84 (dd, J=9.3, 5.2 Hz, 1H), 3.72 (ddd, J=11.9,6.5, 5.5 Hz, 1H), 3.46 (s, 3H), 2.29 (s, 3H), 1.67-1.62 (m, 2H), 1.28(d, J=6.3 Hz, 3H), 1.23-1.17 (m, 2H). MS (ESI−) m/z 263 (M−H)⁻.

Example I-115D1-{2-[(2R)-2-methoxypropoxy]-5-methylphenyl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(R)-1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylic acid(71 mg, 0.269 mmol) from Example I-115C,Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (103 mg, 0.537 mmol) and N,N-dimethylpyridin-4-amine (32.8mg, 0.269 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (55.9 mg, 0.269 mmol). The reaction was stirredat ambient temperature for 16 hours. The reaction mixture was quenchedwith 0.2 mL of 2N aqueous citric acid and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes. Thematerial was dissolved in methanol/dimethyl sulfoxide and was purifiedby reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound as a trifluoroacetic acid salt. ¹H NMR(400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.45 (s, 1H), 9.02 (dd, J=4.2,1.6 Hz, 1H), 8.91 (dt, J=8.7, 1.2 Hz, 1H), 8.34-8.26 (m, 2H), 7.90 (dd,J=8.4, 7.5 Hz, 1H), 7.65 (dd, J=8.8, 4.2 Hz, 1H), 7.04-6.99 (m, 1H),6.93 (d, J=2.1 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 3.56 (dd, J=9.5, 5.9 Hz,1H), 3.31 (dd, J=9.5, 5.2 Hz, 1H), 3.05 (s, 3H), 2.85 (p, J=6.0 Hz, 1H),2.19 (s, 3H), 1.23 (tq, J=9.5, 3.4 Hz, 2H), 1.00-0.92 (m, 1H), 0.88(ddd, J=7.8, 5.5, 2.8 Hz, 1H), 0.75 (d, J=6.3 Hz, 3H). MS (ESI+) m/z 455(M+H)⁺.

Example I-1161-{2-[(2R)-2-methoxypropoxy]-5-methylphenyl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(R)-1-(2-(2-methoxypropoxy)-5-methylphenyl)cyclopropanecarboxylic acid(83 mg, 0.314 mmol) from Example I-115C,Ni-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (120 mg, 0.628 mmol) and N,N-dimethylpyridin-4-amine (38.4mg, 0.314 mmol) in anhydrous dichloromethane (1 mL) was added2-methylquinoline-5-sulfonamide (74 mg, 0.333 mmol). The reaction wasstirred at ambient temperature for 15 hours. The reaction was quenchedwith 0.2 mL of aqueous 2N citric acid and the residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 20 minutes. Thematerial was dissolved in methanol/dimethyl sulfoxide and was purifiedby reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100Å AXIA™ column (30 mm×150 mm). A gradient of acetonitrile (A) and 0.1%trifluoroacetic acid in water (B) was used, at a flow rate of 50mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95%A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A)to provide the title compound as a trifluoroacetic acid salt. ¹H NMR(501 MHz, dimethyl sulfoxide-d₆) δ ppm 11.43 (s, 1H), 8.87 (d, J=8.9 Hz,1H), 8.24 (ddt, J=7.4, 2.6, 1.1 Hz, 2H), 7.89 (dd, J=8.3, 7.6 Hz, 1H),7.61 (d, J=8.9 Hz, 1H), 7.03 (ddd, J=8.2, 2.3, 0.8 Hz, 1H), 6.94 (d,J=2.1 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 3.60 (dd, J=9.5, 6.0 Hz, 1H),3.37 (dd, J=9.4, 5.2 Hz, 1H), 3.07 (s, 3H), 2.90 (dt, J=11.8, 6.0 Hz,1H), 2.72 (s, 3H), 2.21 (s, 3H), 1.31-1.20 (m, 2H), 0.97 (ddd, J=10.1,5.9, 3.2 Hz, 1H), 0.90 (ddd, J=8.2, 5.8, 3.0 Hz, 1H), 0.79 (d, J=6.3 Hz,3H). MS (ESI+) m/z 469 (M+H)⁺. (R) absolute stereochemistry confirmed byX-ray analysis.

Example I-1171-(5-ethyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-117A (S)-3-(2-bromo-4-ethylphenoxy)tetrahydrofuran

In a 100 mL flask was added 2-bromo-4-ethylphenol (0.685 g, 3.41 mmol)from Example I-111A and triphenylphosphine (1.429 g, 5.45 mmol) intetrahydrofuran (16 mL). The mixture was stirred briefly at ambienttemperature, under nitrogen, and (E)-diisopropyldiazene-1,2-dicarboxylate (1.073 mL, 5.45 mmol) was added. The mixturewas stirred briefly under nitrogen at ambient temperature and(R)-tetrahydrofuran-3-ol (0.3 g, 3.41 mmol) was added dropwise. Thereaction mixture was stirred overnight at ambient temperature. Thesolvent was removed under reduced pressure rude material was purified bychromatography, eluting on 24 g silica gel cartridge with a gradient of0-30% ethyl acetate/heptanes over a period of 10 minutes to provide thetitle compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.39 (d, J=2.1 Hz,1H), 7.05 (dd, J=8.3, 2.2 Hz, 1H), 6.76 (d, J=8.3 Hz, 1H), 4.92 (ddt,J=6.8, 4.8, 2.4 Hz, 1H), 4.07-3.98 (m, 3H), 3.93 (td, J=8.1, 4.2 Hz,1H), 2.57 (q, J=7.6 Hz, 2H), 2.26-2.11 (m, 2H), 1.20 (t, J=7.6 Hz, 3H).MS (APCI+) m/z 271 (M+H)⁺.

Example I-117B (S)-methyl1-(5-ethyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylate

To a solution of (S)-3-(2-bromo-4-ethylphenoxy)tetrahydrofuran (0.39 g,1.438 mmol) from Example I-117A in tetrahydrofuran (6 mL) was addedbis(dibenzylideneacetone)palladium (0.017 g, 0.029 mmol) and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.020 g,0.029 mmol). Nitrogen was bubbled through the solution for about 3minutes, and a 0.45 M in tetrahydrofuran solution of(1-(methoxycarbonyl)cyclopropyl)zinc(II) bromide (6.39 mL, 2.88 mmol)was added dropwise over 2 minutes. The reaction was stirred for 4 hoursat 50° C. The reaction was quenched with saturated ammonium chloride (60mL), diluted with ethyl acetate (40 mL) and the layers were separated.The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The crude material was purified viachromatography on a 24 g silica gel cartridge, eluting with ethylacetate in heptane at 0-100% gradient over a period of 12 minutes toprovide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.05(dd, J=8.2, 2.3 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H),4.96 (tt, J=5.0, 2.1 Hz, 1H), 4.02 (dd, J=10.0, 4.8 Hz, 1H), 3.94-3.84(m, 3H), 3.59 (s, 3H), 2.58 (q, J=7.6 Hz, 2H), 2.19-2.09 (m, 2H),1.62-1.53 (m, 2H), 1.21 (t, J=7.6 Hz, 3H), 1.14-1.05 (m, 2H). MS (APCI+)m/z 291 (M+H)⁺.

Example I-117C(S)-1-(5-ethyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicacid

(S)-Methyl1-(5-ethyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylate(0.375 g, 1.292 mmol) from Example I-117B was dissolved intetrahydrofuran (1.5 mL), methanol (1.5 mL), and water (1.5 mL) andtreated with sodium hydroxide (0.258 g, 6.46 mmol). The reaction wasstirred at 35° C. for 15 hours, concentrated, cooled in an ice bath andcarefully quenched with 1N aqueous citric acid (about 3.6 mL) until thepH ˜5. The resulting slurry was extracted with dichloromethane. Thedichloromethane layer was concentrated and azeotroped with toluene 3×10mL to provide the title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm7.09-7.01 (m, 2H), 6.69 (d, J=9.0 Hz, 1H), 4.98-4.93 (m, 1H), 4.03 (dd,J=10.0, 4.8 Hz, 1H), 3.95-3.87 (m, 3H), 2.57 (q, J=7.6 Hz, 2H),2.18-2.10 (m, 2H), 1.63 (q, J=3.9 Hz, 2H), 1.20 (t, J=7.6 Hz, 2H),1.17-1.12 (m, 2H). MS (APCI+) m/z 277 (M+H)⁺.

Example I-117D1-(5-ethyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(S)-1-(5-ethyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicacid (70 mg, 0.253 mmol) from Example I-117C,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (97 mg, 0.507 mmol) and N,N-dimethylpyridin-4-amine (34.0mg, 0.279 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (52.8 mg, 0.253 mmol). After 16 hours, thereaction was quenched with 1 mL of 1N aqueous citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes, The crudematerial was triturated with diethyl ether (1.5 mL) and filtered toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.52 (s, 1H), 9.04 (dd, J=4.3, 1.6 Hz, 1H), 8.95 (d, J=8.6 Hz, 1H),8.32 (dd, J=13.3, 8.0 Hz, 2H), 7.92 (t, J=8.0 Hz, 1H), 7.68 (dd, J=8.8,4.2 Hz, 1H), 7.10-7.03 (m, 1H), 6.98 (d, J=2.2 Hz, 1H), 6.73 (d, J=8.3Hz, 1H), 4.64 (t, J=5.6 Hz, 1H), 3.63 (dd, J=9.9, 4.9 Hz, 1H), 3.55 (td,J=8.1, 3.5 Hz, 1H), 3.43 (td, J=8.6, 6.3 Hz, 1H), 3.19 (dd, J=9.8, 2.0Hz, 1H), 2.53 (q, J=7.6 Hz, 1H), 1.78 (dtd, J=17.5, 8.6, 6.1 Hz, 1H),1.39 (m, 1H), 1.26 (ddd, J=9.2, 6.3, 3.6 Hz, 1H), 1.16 (t, J=7.6 Hz,3H), 0.93 (d, J=21.4 Hz, 2H). MS (APCI+) m/z 467 (M+H)⁺.

Example I-1181-(5-ethyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-118A 2-bromo-4-ethyl-1-(methoxymethoxy)benzene

2-Bromo-4-ethylphenol (3.3 g, 16.41 mmol) from Example I-111A wasdissolved in dichloromethane (41.0 mL). The mixture was cooled to 0° C.(ice/water bath) and chloro(methoxy)methane (6.23 mL, 82 mmol) was addedvia syringe in one portion. N,N-Diisopropylethylamine (14.29 mL, 82mmol) was added dropwise over 15 minutes. The resulting mixture wasstirred at 0° C. for 10 minutes, allowed to warm to room-temperature andstirred under argon for 18 hours. The reaction mixture was quenched withsaturated aqueous sodium bicarbonate (100 mL) and extracted withdichloromethane (2×100 mL). The organic extracts were combined, washedwith water (1×100 mL) and brine (1×100 mL), dried over anhydrousmagnesium sulfate and filtered. The solvent was removed in vacuo and theresidue was purified on a 80 g silica gel cartridge eluting with agradient of 0-20% ethyl acetate/heptanes to provide the title compound.¹H NMR (501 MHz, chloroform-d) δ ppm 7.38 (dd, J=1.4, 0.8 Hz, 1H), 7.06(d, J=1.1 Hz, 2H), 5.21 (s, 2H), 3.52 (s, 3H), 2.57 (qd, J=7.7, 0.6 Hz,2H), 1.20 (t, J=7.6 Hz, 3H).

Example I-118B Methyl1-(5-ethyl-2-(methoxymethoxy)phenyl)cyclopropanecarboxylate

2-Bromo-4-ethyl-1-(methoxymethoxy)benzene (2.02 g, 8.24 mmol) fromExample I-118A was dissolved in tetrahydrofuran (33.0 mL), and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.117 g,0.165 mmol) and bis(dibenzylideneacetone)palladium (0.095 g, 0.165 mmol)were added. Nitrogen was bubbled through the solution for 10 minutes. Asolution of freshly-prepared (1-(methoxycarbonyl)cyclopropyl)zinc(II)bromide (36.6 mL, 16.48 mmol) in tetrahydrofuran was added dropwise. Thereaction was stirred at 50° C. for 2 hours and at 45° C. for 15 hours.The reaction was cooled and quenched with saturated aqueous ammoniumchloride (40 mL), and diluted with methyl tert-butyl ether (100 mL). Theaqueous layer was extracted once more with methyl tert-butyl ether (100mL). The combined organic layer was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by silica gel chromatography, eluting with 0-20% ethylacetate/heptanes to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.10-6.96 (m, 3H), 5.17 (s, 2H), 3.60 (s, 3H), 3.45(s, 3H), 2.58 (q, J=7.6 Hz, 2H), 1.60 (q, J=4.1 Hz, 2H), 1.29-1.19 (m,3H), 1.16-1.12 (m, 2H).

Example I-118C Methyl 1-(5-ethyl-2-hydroxyphenyl)cyclopropanecarboxylate

To a cooled 0° C. solution of methyl1-(5-ethyl-2-(methoxymethoxy)phenyl)cyclopropanecarboxylate (2.16 g,8.17 mmol) from Example I-118B in methanol (82 mL) was added 4 N aqueoushydrogen chloride (8.17 mL, 32.7 mmol) in dioxane and the reaction wasstirred at ambient temperature for 4 hours. The reaction wasconcentrated and purified by silica gel chromatography, eluting with0-20% ethyl acetate/heptanes to provide the title compound. ¹H NMR (501MHz, chloroform-d) δ ppm 7.09-7.02 (m, 2H), 6.84 (d, J=8.0 Hz, 1H), 5.63(s, 1H), 3.69 (d, J=0.5 Hz, 3H), 2.60 (q, J=7.6 Hz, 2H), 1.72-1.66 (m,2H), 1.29-1.20 (m, 5H).

Example I-118D (R)-methyl1-(5-ethyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylate

In a 100 mL flask was added methyl1-(5-ethyl-2-hydroxyphenyl)cyclopropanecarboxylate (0.5 g, 2.270 mmol)from Example I-118C and triphenylphosphine (0.953 g, 3.63 mmol) intetrahydrofuran (10 mL). The mixture was stirred briefly at ambienttemperature under nitrogen, and (E)-diisopropyldiazene-1,2-dicarboxylate (0.715 mL, 3.63 mmol) was added. The mixturewas stirred briefly under nitrogen at ambient temperature and(S)-tetrahydrofuran-3-ol (0.181 mL, 2.270 mmol) was added dropwise. Thereaction mixture was stirred for 16 hours at ambient temperature. Thesolvent was removed under reduced pressure. The residue was purified bychromatography, eluting on a 24 g silica gel cartridge with a gradientof 0-100% ethyl acetate/heptanes over a period of 10 minutes to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.05 (dd,J=8.1, 2.2 Hz, 1H), 7.03 (d, J=2.2 Hz, 1H), 6.68 (d, J=8.1 Hz, 1H), 4.95(tt, J=5.0, 2.2 Hz, 1H), 4.02 (dd, J=10.0, 4.8 Hz, 1H), 3.96-3.83 (m,3H), 3.59 (s, 3H), 2.58 (q, J=7.6 Hz, 2H), 2.22-2.08 (m, 2H), 1.62-1.51(m, 3H), 1.21 (t, J=7.6 Hz, 3H), 1.15-1.04 (m, 2H). MS (APCI+) m/z 291(M+H)⁺.

Example I-118E(R)-1-(5-ethyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicAcid

(R)-Methyl1-(5-ethyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylate(0.44 g, 1.515 mmol) from Example I-118D was dissolved intetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL) and treatedwith sodium hydroxide (0.303 g, 7.58 mmol). The reaction was stirred at35° C. overnight, concentrated, cooled in an ice bath and carefullyquenched with 1N aqueous citric acid (about 4 mL) until the pH ˜5. Theresulting slurry was extracted with dichloromethane. The dichloromethanelayer was concentrated and azeotroped with toluene 3×10 mL to providethe title compound. ¹H NMR (501 MHz, chloroform-d) δ ppm 7.07-7.02 (m,2H), 6.68 (d, J=9.0 Hz, 1H), 4.95 (td, J=6.2, 5.8, 4.0 Hz, 1H), 4.03(dd, J=10.0, 4.8 Hz, 1H), 3.94-3.86 (m, 3H), 2.57 (q, J=7.6 Hz, 2H),2.14 (td, J=7.3, 6.8, 4.4 Hz, 2H), 1.64-1.59 (m, 2H), 1.20 (t, J=7.6 Hz,3H), 1.15 (m, 2H). MS (APCI+) m/z 277 (M+H)⁺.

Example I-118F1-(5-ethyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(R)-1-(5-ethyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicacid (70 mg, 0.253 mmol) from Example I-118E,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (97 mg, 0.507 mmol) and N,N-dimethylpyridin-4-amine (34.0mg, 0.279 mmol) in anhydrous dichloromethane (1 mL) was addedquinoline-5-sulfonamide (52.8 mg, 0.253 mmol). After 16 hours, thereaction was quenched with 1 mL of 1N aqueous citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. Thematerial was triturated with diethyl ether (1.5 mL) and filtered toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.52 (s, 1H), 9.04 (dd, J=4.3, 1.6 Hz, 1H), 8.95 (d, J=8.6 Hz, 1H),8.32 (dd, J=13.3, 8.0 Hz, 2H), 7.92 (t, J=8.0 Hz, 1H), 7.68 (dd, J=8.8,4.2 Hz, 1H), 7.10-7.03 (m, 1H), 6.98 (d, J=2.2 Hz, 1H), 6.73 (d, J=8.3Hz, 1H), 4.64 (t, J=5.6 Hz, 1H), 3.63 (dd, J=9.9, 4.9 Hz, 1H), 3.55 (td,J=8.1, 3.5 Hz, 1H), 3.43 (td, J=8.6, 6.3 Hz, 1H), 3.19 (dd, J=9.8, 2.0Hz, 1H), 2.53 (q, J=7.6 Hz, 1H), 1.78 (dtd, J=17.5, 8.6, 6.1 Hz, 1H),1.39 (m, 1H), 1.26 (ddd, J=9.2, 6.3, 3.6 Hz, 1H), 1.16 (t, J=7.6 Hz,3H), 0.93 (d, J=21.4 Hz, 2H). MS (APCI+) m/z 467 (M+H)⁺.

Example I-1191-(5-ethyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(R)-1-(5-ethyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicacid (70 mg, 0.253 mmol) from Example I-118E,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (97 mg, 0.507 mmol) and N,N-dimethylpyridin-4-amine (34.0mg, 0.279 mmol) in anhydrous dichloromethane (1 mL) was added2-methylquinoline-5-sulfonamide (56.3 mg, 0.253 mmol). After 16 hours,the reaction was quenched with 1 mL of 1N aqueous citric acid and theorganic layer was concentrated in vacuo. The residue was purified viachromatography on a 12 g silica gel cartridge, eluting with a gradientof 0-10% methanol/dichloromethane over a period of 10 minutes. Thematerial was triturated with diethyl ether (0.5 mL) and filtered toprovide the title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δppm 11.45 (s, 1H), 8.83 (d, J=8.9 Hz, 1H), 8.21 (t, J=7.2 Hz, 2H), 7.86(t, J=7.9 Hz, 1H), 7.56 (d, J=8.9 Hz, 1H), 7.06 (dd, J=8.4, 2.2 Hz, 1H),6.98 (d, J=2.2 Hz, 1H), 6.73 (d, J=8.3 Hz, 1H), 4.66 (td, J=4.7, 2.4 Hz,1H), 3.65 (dd, J=9.9, 4.9 Hz, 1H), 3.56 (td, J=8.1, 3.5 Hz, 1H), 3.44(td, J=8.6, 6.4 Hz, 1H), 3.21 (dd, J=9.8, 2.0 Hz, 1H), 2.71 (s, 3H),2.53 (q, J=7.6 Hz, 1H), 1.86-1.72 (m, 1H), 1.40 (m, 1H), 1.26 (m, 2H),1.16 (t, J=7.6 Hz, 3H), 0.92 (dd, J=24.2, 8.0 Hz, 2H). MS (APCI+) m/z481 (M+H)⁺.

Example I-1221-(5-methyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-122A 2-bromo-1-(methoxymethoxy)-4-methylbenzene

To a cooled (ice/water bath) solution of 2-bromo-4-methylphenol (5.27 g,27.6 mmol) in dichloromethane (69.0 mL) was added chloro(methoxy)methane(10.49 mL, 138 mmol) via syringe in one portion.N,N-Diisopropylethylamine (24.05 mL, 138 mmol) was added dropwise over15 minutes. The resulting mixture was stirred at 0° C. for 10 minutes,allowed to warm to room-temperature and stirred under argon for 40minutes. The reaction mixture was quenched with saturated aqueous sodiumbicarbonate (100 mL) and extracted with dichloromethane (2×100 mL). Theorganic extracts were combined, washed with water (1×100 mL) and brine(1×100 mL), dried over anhydrous magnesium sulfate and filtered. Thesolvent was removed in vacuo. The crude material was purified on an 80 gsilica gel cartridge eluting with a gradient 0-20% ethylacetate/heptanes to provide the title compound. ¹H NMR (400 MHz,chloroform-d) δ ppm 7.36 (d, J=1.1 Hz, 1H), 7.03 (d, J=1.1 Hz, 2H), 5.20(s, 2H), 3.51 (s, 3H), 2.27 (s, 3H).

Example I-122B Methyl1-(2-(methoxymethoxy)-5-methylphenyl)cyclopropanecarboxylate

2-Bromo-1-(methoxymethoxy)-4-methylbenzene (2.3 g, 9.95 mmol) fromExample I-122A was dissolved in tetrahydrofuran (39.8 mL), and Q-Phos(1,2,3,4,5-pentaphenyl-1′-(di-tert-butylphosphino)ferrocene) (0.141 g,0.199 mmol) and bis(dibenzylideneacetone)palladium (0.114 g, 0.199 mmol)were added. The reaction was sparged with nitrogen 10 minutes. Asolution of freshly-prepared (1-(methoxycarbonyl)cyclopropyl)zinc(II)bromide (45.2 mL, 19.91 mmol) in tetrahydrofuran was added dropwise. Thereaction mixture was stirred at 50° C. for 30 minutes and at 45° C. for15 hours. The reaction was cooled to ambient temperature and quenchedwith saturated aqueous ammonium chloride (40 mL). The mixture wasdiluted with methyl tert-butyl ether. The aqueous layer was extractedonce with methyl tert-butyl ether. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The crude material was purified by flash column chromatography, elutingwith 0-20% ethyl acetate/heptanes to provide the title compound. ¹H NMR(501 MHz, chloroform-d) δ ppm 7.06-6.99 (m, 2H), 6.97 (d, J=8.1 Hz, 1H),5.16 (s, 2H), 3.60 (s, 3H), 3.45 (s, 3H), 2.28 (s, 3H), 1.63-1.57 (m,2H), 1.12 (q, J=4.1 Hz, 2H).

Example I-122C Methyl1-(2-hydroxy-5-methylphenyl)cyclopropanecarboxylate

Into a 200 mL flask was added methyl1-(2-(methoxymethoxy)-5-methylphenyl)cyclopropanecarboxylate (2.5 g,9.99 mmol) from Example I-122B and methanol (100 mL). The reaction wascooled to 0° C. and 4N hydrogen chloride (9.99 mL, 40.0 mmol) in dioxanewas added. The reaction was stirred at ambient temperature for 15 hoursand concentrated. The residue was purified by silica gel chromatography,eluting with 0-20% ethyl acetate/heptanes to provide the title compound.¹H NMR (501 MHz, chloroform-d) δ ppm 7.02-6.96 (m, 2H), 6.80-6.75 (m,1H), 5.58 (s, 1H), 3.65 (s, 3H), 2.25 (s, 3H), 1.71-1.60 (m, 2H),1.26-1.18 (m, 2H).

Example I-122D (R)-methyl1-(5-methyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylate

In a 20 mL vial was added methyl1-(2-hydroxy-5-methylphenyl)cyclopropanecarboxylate (0.2 g, 0.970 mmol)from Example I-122C and triphenylphosphine (0.407 g, 1.552 mmol) intetrahydrofuran (4.85 mL). The mixture was stirred briefly at ambienttemperature under nitrogen, and (E)-diisopropyldiazene-1,2-dicarboxylate (0.305 mL, 1.552 mmol) was added. The mixturewas stirred briefly under nitrogen at ambient temperature and(S)-tetrahydrofuran-3-ol (0.093 mL, 1.164 mmol) was added dropwise. Thereaction mixture was stirred at ambient temperature for 15 hours. Thesolvent was removed under reduced pressure. The crude material waspurified by chromatography, eluting on 24 g silica gel cartridge with agradient of 0-30% ethyl acetate/heptanes to provide the title compound.¹H NMR (501 MHz, chloroform-d) δ ppm 7.07-7.03 (m, 2H), 6.69 (d, J=8.0Hz, 1H), 4.98 (tt, J=4.9, 2.1 Hz, 1H), 4.04 (dd, J=10.0, 4.8 Hz, 1H),3.98-3.87 (m, 3H), 3.62 (s, 3H), 2.30 (s, 3H), 2.20-2.11 (m, 2H),1.64-1.55 (m, 2H), 1.18-1.05 (m, 2H). MS (ESI+) m/z 277 (M+H)⁺.

Example I-122E(R)-1-(5-methyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicAcid

(R)-methyl1-(5-methyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylate(0.245 g, 0.887 mmol) from Example I-122D was dissolved intetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL), treated withsodium hydroxide (0.177 g, 4.43 mmol) and stirred at ambient temperaturefor 72 hours. The reaction was reduced in volume, cooled in an ice bathand carefully quenched with 2N aqueous citric acid (about 3 mL, dilutedwith ice) until the pH was acidic. The resulting mixture was stirredvigorously, the water was decanted, and the material was washed withwater and dried under a stream of nitrogen to provide the titlecompound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.10-6.96 (m, 2H), 6.67(d, J=8.8 Hz, 1H), 5.06-4.89 (m, 1H), 4.10-3.99 (m, 1H), 3.99-3.84 (m,3H), 2.28 (s, 3H), 2.23-2.07 (m, 2H), 1.69-1.57 (m, 2H), 1.35-1.19 (m,1H), 1.19-1.07 (m, 2H). MS (ESI−) m/z 260 (M−H)⁻.

Example I-122F1-(5-methyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(R)-1-(5-methyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicacid (50 mg, 0.191 mmol) from Example I-122E,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (73.1 mg, 0.381 mmol) and N,N-dimethylpyridin-4-amine(23.29 mg, 0.191 mmol) in anhydrous N,N-dimethylformamide (1 mL) wasadded quinoline-5-sulfonamide (43 mg, 0.206 mmol). The reaction wasstirred at ambient temperature overnight, dissolved in methanol/dimethylsulfoxide and purified by reverse-phase preparative HPLC on aPhenomenex® Luna® C8(2) 5 μm 100A AXIA™ column (30 mm×150 mm). Agradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B)was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0minutes linear gradient 95-10% A) to provide the title compound. ¹H NMR(400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.50 (s, 1H), 9.02 (dd, J=4.2,1.6 Hz, 1H), 8.92 (dt, J=8.8, 1.2 Hz, 1H), 8.35-8.26 (m, 2H), 7.91 (dd,J=8.4, 7.5 Hz, 1H), 7.66 (dd, J=8.8, 4.2 Hz, 1H), 7.01 (dd, J=8.4, 2.2Hz, 1H), 6.94 (d, J=2.1 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 4.59 (ddd,J=6.5, 4.3, 2.0 Hz, 1H), 3.59 (dd, J=9.9, 4.8 Hz, 1H), 3.52 (td, J=8.1,3.5 Hz, 1H), 3.41 (td, J=8.6, 6.3 Hz, 1H), 3.15 (dd, J=9.9, 2.0 Hz, 1H),2.20 (s, 3H), 1.83-1.68 (m, 1H), 1.37 (dddd, J=12.9, 5.6, 3.4, 1.6 Hz,1H), 1.20 (qdd, J=9.2, 5.7, 3.0 Hz, 2H), 0.92 (ddd, J=9.6, 5.7, 3.1 Hz,1H), 0.85 (ddd, J=8.5, 5.7, 2.9 Hz, 1H). MS (ESI+) m/z 453 (M+H)⁺.

Example I-1231-(5-methyl-2-{[(3R)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(R)-1-(5-methyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicacid (50 mg, 0.191 mmol) from Example I-122E,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (73.1 mg, 0.381 mmol) and N,N-dimethylpyridin-4-amine(23.29 mg, 0.191 mmol) in anhydrous N,N-dimethylformamide (1 mL) wasadded 2-methylquinoline-5-sulfonamide (42.4 mg, 0.191 mmol). Thereaction mixture was stirred at ambient temperature for 16 hours,dissolved in methanol/dimethyl sulfoxide, and purified by reverse-phasepreparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column(30 mm×150 mm). A gradient of acetonitrile (A) and 0.1% trifluoroaceticacid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A) to providethe title compound. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ ppm 11.48(s, 1H), 8.91 (d, J=8.9 Hz, 1H), 8.28-8.20 (m, 2H), 7.90 (t, J=8.0 Hz,1H), 7.64 (d, J=9.0 Hz, 1H), 7.04-6.99 (m, 1H), 6.93 (d, J=2.2 Hz, 1H),6.70 (d, J=8.3 Hz, 1H), 4.65 (ddt, J=6.5, 4.2, 1.9 Hz, 1H), 3.64 (dd,J=9.8, 4.8 Hz, 1H), 3.54 (td, J=8.1, 3.5 Hz, 1H), 3.46-3.38 (m, 1H),3.19 (dd, J=9.9, 2.0 Hz, 1H), 2.73 (s, 3H), 2.20 (s, 3H), 1.79 (dddd,J=13.1, 9.3, 8.2, 6.1 Hz, 1H), 1.42 (dddd, J=12.7, 5.5, 3.5, 1.6 Hz,1H), 1.20 (th, J=9.0, 2.8 Hz, 2H), 0.92 (ddd, J=9.5, 5.7, 3.1 Hz, 1H),0.86 (ddd, J=8.5, 5.6, 2.8 Hz, 1H). MS (ESI+) m/z 467 (M+H)⁺.

Example I-1241-(5-methyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamideExample I-124A (S)-methyl1-(5-methyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylate

Into a 20 mL vial was added methyl1-(2-hydroxy-5-methylphenyl)cyclopropanecarboxylate (0.2 g, 0.970 mmol)from Example I-122C and triphenylphosphine (0.407 g, 1.552 mmol) intetrahydrofuran. The mixture was stirred briefly at ambient temperatureunder nitrogen, and (E)-diisopropyl diazene-1,2-dicarboxylate (0.305 mL,1.552 mmol) was added. The mixture was stirred briefly under nitrogen atambient temperature and (R)-tetrahydrofuran-3-ol (0.093 mL, 1.164 mmol)was added dropwise. The reaction mixture was stirred for 16 hours atambient temperature. The solvent was removed under reduced pressure. Thecrude material was purified by chromatography, eluting on 24 g silicagel cartridge with a gradient of 0-30% ethyl acetate/heptanes to providethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 7.08-6.97 (m,2H), 6.70-6.63 (m, 1H), 5.02-4.93 (m, 1H), 4.03 (dd, J=9.9, 4.7 Hz, 1H),3.97-3.83 (m, 3H), 3.61 (s, 3H), 2.29 (s, 3H), 2.20-2.11 (m, 2H),1.63-1.53 (m, 2H), 1.16-1.03 (m, 2H). MS (ESI+) m/z 277 (M+H)⁺.

Example I-124B(S)-1-(5-methyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicacid

(S)-Methyl1-(5-methyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylate(0.265 g, 0.96 mmol) from Example I-124A was dissolved intetrahydrofuran (2 mL), methanol (2 mL), and water (2 mL) and treatedwith sodium hydroxide (0.192 g, 4.80 mmol) and stirred at 70° C. for 45minutes. The reaction was reduced in volume, cooled in an ice bath andcarefully quenched with 2N aqueous citric acid (about 3 mL, diluted withice) until the pH was acidic. The resulting material was stirredvigorously and the water was decanted. The material was washed withwater and dried under a stream of nitrogen to provide the titlecompound. ¹H NMR (500 MHz, chloroform-d) δ ppm 7.07-7.03 (m, 2H),6.72-6.65 (m, 1H), 5.02-4.93 (m, 1H), 4.04 (dd, J=10.0, 4.8 Hz, 1H),3.98-3.89 (m, 3H), 2.29 (s, 3H), 2.22-2.11 (m, 2H), 1.67-1.60 (m, 2H),1.20-1.14 (m, 2H).

Example I-124C1-(5-methyl-2-{[(3S)-oxolan-3-yl]oxy}phenyl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of(S)-1-(5-methyl-2-((tetrahydrofuran-3-yl)oxy)phenyl)cyclopropanecarboxylicacid (50 mg, 0.191 mmol) from Example I-124B,N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (73.1 mg, 0.381 mmol) and N,N-dimethylpyridin-4-amine(23.29 mg, 0.191 mmol) in anhydrous N,N-dimethylformamide (1 mL) wasadded 2-methylquinoline-5-sulfonamide (45 mg, 0.202 mmol). The reactionwas stirred at ambient temperature for 15 hours, dissolved inmethanol/dimethyl sulfoxide and purified by reverse-phase preparativeHPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×150mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid inwater (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A,0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A,10.0-12.0 minutes linear gradient 95-10% A) to provide the titlecompound as a trifluoroacetic acid salt. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) 6 ppm 11.48 (s, 1H), 8.88 (d, J=8.9 Hz, 1H), 8.27-8.17 (m,2H), 7.88 (t, J=8.0 Hz, 1H), 7.61 (d, J=8.9 Hz, 1H), 7.02 (dd, J=8.3,2.1 Hz, 1H), 6.93 (d, J=2.2 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 4.64 (ddt,J=6.5, 4.2, 1.9 Hz, 1H), 3.63 (dd, J=9.9, 4.9 Hz, 1H), 3.54 (td, J=8.1,3.5 Hz, 1H), 3.42 (td, J=8.6, 6.4 Hz, 1H), 3.18 (dd, J=9.8, 2.0 Hz, 1H),2.71 (s, 3H), 2.20 (s, 3H), 1.87-1.69 (m, 1H), 1.41 (ddt, J=12.3, 5.4,2.7 Hz, 1H), 1.20 (qdd, J=9.1, 5.7, 3.0 Hz, 2H), 0.92 (ddd, J=9.5, 5.7,3.1 Hz, 1H), 0.85 (ddd, J=8.6, 5.7, 2.9 Hz, 1H). MS (ESI+) m/z 467(M+H)⁺.

TABLE 1 Example Name NMR MS Example 1-(3- ¹H NMR (400 MHz, DMSO-d₆:D₂O =9:1 (v/v)) MS (APCI+) II-1 methoxyphenyl)- δ ppm 8.57-8.45 (m, 1H),8.35-8.22 (m, 2H), m/z 382.1 N-(naphthalene-1- 8.18-8.06 (m, 1H),7.76-7.63 (m, 3H), 7.15 (M + H)⁺. sulfonyl)cyclopropane-1- (dd, J = 8.4,7.3 Hz, 1H), 6.81 (ddd, J = 8.3, 2.5, carboxamide 1.0 Hz, 1H), 6.71-6.59(m, 2H), 3.67 (s, 3H), 1.27-1.15 (m, 2H), 1.15-0.96 (m, 2H). Example1-(3-methoxy-4- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+)II-2 methylphenyl)-N- δ ppm 8.55-8.42 (m, 1H), 8.34-8.21 (m, 2H), m/z396.1 (naphthalene-1- 8.18-8.05 (m, 1H), 7.76-7.60 (m, 3H), 6.98 (M +H)⁺. sulfonyl)cyclopropane-1- (dd, J = 7.5, 0.9 Hz, 1H), 6.62 (d, J =1.7 Hz, carboxamide 1H), 6.59 (dd, J = 7.6, 1.7 Hz, 1H), 3.72 (s, 3H),2.10 (s, 3H), 1.23-1.12 (m, 2H), 1.10-0.95 (m, 2H). ExampleN-(quinoline-5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.99 (s, MS (ESI+) II-3sulfonyl)-1-[2- 1H), 8.99 (dd, J = 4.2, 1.6 Hz, 1H), 8.70 (dd, J = m/z451 (trifluoromethoxy) 8.7, 1.5 Hz, 1H), 8.35 (t, J = 8.2 Hz, 2H),7.98-7.88 (M + H)⁺. phenyl]cyclobutane- (m, 1H), 7.68 (dd, J = 7.6, 1.9Hz, 1H), 7.51 1-carboxamide (dd, J = 8.8, 4.2 Hz, 1H), 7.39 (dtd, J =19.5, 7.5, 1.6 Hz, 2H), 7.00-6.90 (m, 1H), 2.46 (ddd, J = 10.8, 5.8, 3.4Hz, 2H), 2.30-2.20 (m, 2H), 1.76-1.52 (m, 2H). Example 1-(1-ethyl-3- ¹HNMR (500 MHz, DMSO-d₆) δ ppm 8.60-8.57 MS (ESI) II-4 methyl-1H- (m, 1H),8.30-8.27 (m, 1H), 8.26 (dd, J = 7.4, 1.2 m/z 384 pyrazol-5-yl)-N- Hz,1H), 8.13-8.10 (m, 1H), 7.74-7.66 (m, 3H), (M + H)⁺. (naphthalene-1-5.87 (s, 1H), 3.52 (q, J = 7.2 Hz, 2H), 2.07 (s,sulfonyl)cyclopropane-1- 3H), 1.45-1.42 (m, 2H), 1.10-1.07 (m, 2H), 0.94carboxamide (t, J = 7.2 Hz, 3H). Example 1-(1-ethyl-5- ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.59-8.55 MS (ESI) II-5 methyl-1H- (m, 1H), 8.35-8.31 (m,2H), 8.15-8.12 (m, 1H), m/z 384 pyrazol-3-yl)-N- 7.74-7.66 (m, 3H), 5.73(s, 1H), 4.06 (q, J = 7.2 (M + H)⁺. (naphthalene-1- Hz, 2H), 2.20 (s,3H), 1.41 (t, J = 7.2 Hz, 3H), sulfonyl)cyclopropane-1- 1.29-1.25 (m,2H), 1.11-1.08 (m, 2H). carboxamide Example 1-(2- ¹H NMR (501 MHz,DMSO-d₆) δ ppm MS (ESI+) II-6 methoxyphenyl)- 11.72-11.43 (m, 1H), 8.99(dd, J = 4.2, 1.6 Hz, 1H), m/z 397 N-(quinoline-5- 8.73 (d, J = 8.7 Hz,1H), 8.33 (dd, J = 8.2, 3.7 (M + H)⁺. sulfonyl)cyclobutane- Hz, 2H),7.94 (t, J = 7.9 Hz, 1H), 7.52 (dd, J = 1-carboxamide 8.7, 4.1 Hz, 1H),7.39 (d, J = 7.6 Hz, 1H), 7.30-7.13 (m, 1H), 6.96 (td, J = 7.4, 1.1 Hz,1H), 6.67 (dd, J = 8.2, 1.1 Hz, 1H), 3.09 (s, 3H), 2.37 (ddd, J = 12.1,8.8, 5.8 Hz, 2H), 2.11 (tdd, J = 9.1, 7.0, 2.3 Hz, 2H), 1.70-1.48 (m,2H). Example 1-[2-methoxy-5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.96 (s,MS (ESI+) II-7 (trifluoromethyl)pyridin- 1H), 9.08 (dd, J = 4.2, 1.6 Hz,1H), 8.93-8.86 m/z 452 3-yl]-N- (m, 1H), 8.53 (dt, J = 2.4, 1.2 Hz, 1H),8.39 (dt, J = (M + H)⁺. (quinoline-5- 8.5, 1.1 Hz, 1H), 8.35 (dd, J =7.4, 1.2 Hz, 1H), sulfonyl)cyclopropane-1- 7.98 (dd, J = 8.5, 7.4 Hz,1H), 7.89 (d, J = 2.4 carboxamide Hz, 1H), 7.74 (dd, J = 8.8, 4.2 Hz,1H), 3.46 (s, 3H), 1.31 (q, J = 4.4 Hz, 2H), 1.17-1.06 (m, 2H). Example1-[2-methoxy-5- ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.44 (s, MS (ESI+) II-8(trifluoromethyl)pyridin- 1H), 8.53 (dt, J = 2.4, 1.2 Hz, 1H), 7.91 (d,J = m/z 456 3-yl]-N- 2.4 Hz, 1H), 7.08-6.96 (m, 2H), 6.71 (dd, J = (M +H)⁺. (1,2,3,4- 7.3, 2.1 Hz, 1H), 3.89 (s, 3H), 3.19 (t, J = 5.5 Hz,tetrahydroquinoline-5- 2H), 2.86 (t, J = 6.4 Hz, 2H), 1.87-1.68 (m,sulfonyl)cyclopropane-1- 2H), 1.40 (q, J = 4.3 Hz, 2H), 1.16 (q, J = 4.4Hz, carboxamide 2H). Example 1-[2-methoxy-5- ¹H NMR (500 MHz, DMSO-d₆) δppm 11.91 (s, MS (ESI+) II-9 (trifluoromethyl)pyridin- 1H), 8.79 (d, J =8.9 Hz, 1H), 8.53 (dt, J = 2.3, m/z 466 3-yl]-N-(2- 1.1 Hz, 1H),8.30-8.22 (m, 2H), 7.95-7.87 (m, (M + H)⁺. methylquinoline-5- 2H), 7.64(d, J = 8.9 Hz, 1H), 3.50 (s, 3H), 2.74 sulfonyl)cyclopropane-1- (s,3H), 1.30 (q, J = 4.4 Hz, 2H), 1.11 (q, J = 4.4 carboxamide Hz, 2H).Example 1-(2-methoxy-5- ¹H NMR (501 MHz, DMSO-d₆) δ ppm 11.24 (s, MS(ESI+) II-10 methylpyridin-3- 1H), 7.90 (dd, J = 2.3, 1.0 Hz, 1H), 7.41(d, J = m/z 402 yl)-N-(1,2,3,4- 2.3 Hz, 1H), 7.12-6.95 (m, 2H), 6.73(dd, J = (M + H)⁺. tetrahydroquinoline-5- 7.9, 1.4 Hz, 1H), 3.77 (s,3H), 3.28-3.17 (m, sulfonyl)cyclopropane-1- 2H), 2.89 (t, J = 6.4 Hz,2H), 2.21 (s, 3H), carboxamide 1.83-1.71 (m, 2H), 1.37 (q, J = 4.3 Hz,2H), 1.10-0.96 (m, 2H. Example 1-(2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1(v/v)) MS (APCI+) II-11 methoxyphenyl)- δ ppm 7.38-7.26 (m, 1H), 7.21(dd, J = 7.5, 1.7 m/z 441.1 N-(1,2,3,4- Hz, 1H), 7.15-6.96 (m, 3H), 6.93(td, J = 7.5, (M + H)⁺. tetrahydroquinoline-5- 1.1 Hz, 1H), 6.71 (dd, J= 6.5, 2.8 Hz, 1H), 3.72 sulfonyl)cyclopropane-1- (s, 3H), 3.17 (t, J =5.5 Hz, 2H), 2.85 (t, J = 6.4 carboxamide Hz, 2H), 1.84-1.69 (m, 2H),1.48-1.26 (m, 2H), 1.12-0.92 (m, 2H). Example 1-(5-cyclobutyl-2- ¹H NMR(400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-12 methoxypyridin-3- δppm 8.44 (s, 1H), 8.03 (dd, J = 8.1, 1.1 Hz, m/z 441.0(M +yl)-N-(1-methyl- 1H), 7.97-7.85 (m, 2H), 7.53-7.40 (m, 2H), H)⁺.1H-benzimidazole-7- 3.92 (s, 3H), 3.48 (p, J = 8.7 Hz, 1H), 3.41 (s,sulfonyl)cyclopropane-1- 3H), 2.33-2.21 (m, 2H), 2.21-2.04 (m, 2H),carboxamide 2.04-1.89 (m, 1H), 1.89-1.75 (m, 1H), 1.36 (q, J = 4.3 Hz,2H), 1.06 (q, J = 4.5 Hz, 2H). Example 1-(5-cyclobutyl-2- ¹H NMR (400MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-13 methoxypyridin-3- δ ppm8.32 (s, 1H), 8.18 (dd, J = 8.0, 1.1 Hz, m/z 441.0 yl)-N-(1-methyl- 1H),8.06 (dd, J = 7.5, 1.1 Hz, 1H), 7.92 (d, J = (M + H)⁺. 1H-indazole-7-2.3 Hz, 1H), 7.48 (d, J = 2.3 Hz, 1H), 7.35 (t, J =sulfonyl)cyclopropane-1- 7.8 Hz, 1H), 4.11 (s, 3H), 3.47 (p, J = 8.7 Hz,carboxamide 1H), 3.33 (s, 3H), 2.27 (qt, J = 8.0, 2.5 Hz, 2H), 2.20-2.04(m, 2H), 2.04-1.89 (m, 1H), 1.89-1.74 (m, 1H), 1.36 (q, J = 4.3 Hz, 2H),1.27-0.98 (m, 2H). Example 1-(5-cyclobutyl-2- ¹H NMR (400 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-14 methoxypyridin-3- δ ppm 7.92(d, J = 2.3 Hz, 1H), 7.85-7.75 (m, m/z 440.1 yl)-N-(1-methyl- 1H), 7.62(d, J = 7.5 Hz, 1H), 7.55 (d, J = 3.1 Hz, (M + H)⁺. 1H-indole-4- 1H),7.41 (d, J = 2.4 Hz, 1H), 7.32 (t, J = 7.9 Hz, sulfonyl)cyclopropane-1-1H), 6.78 (dd, J = 3.0, 0.8 Hz, 1H), 3.87 (s, 3H), carboxamide 3.60 (s,3H), 3.46 (p, J = 8.8 Hz, 1H), 2.34-2.18 (m, 2H), 2.18-1.89 (m, 3H),1.89-1.74 (m, 1H), 1.28 (q, J = 4.4 Hz, 2H), 1.02 (q, J = 4.5 Hz, 2H).Example 1-(5-cyclobutyl-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS(APCI+) II-15 methoxypyridin-3- δ ppm 8.33 (d, J = 1.0 Hz, 1H),7.99-7.88 (m, m/z 427.1(M + yl)-N-(1H- 2H), 7.71 (dd, J = 7.3, 0.8 Hz,1H), 7.57 (dd, J = H)⁺. indazole-4- 8.4, 7.3 Hz, 1H), 7.42 (d, J = 2.4Hz, 1H), 3.53 sulfonyl)cyclopropane-1- (s, 3H), 3.46 (q, J = 8.8 Hz,1H), 2.33-2.20 (m, carboxamide 2H), 2.20-2.03 (m, 2H), 2.03-1.89 (m,1H), 1.88-1.74 (m, 1H), 1.29 (q, J = 4.3 Hz, 2H), 1.04 (q, J = 4.5 Hz,2H). Example 1-(5-cyclobutyl-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1(v/v)) MS (APCI+) II-16 methoxypyridin-3- δ ppm 8.09-7.86 (m, 4H), 7.82(d, J = 2.4 Hz, m/z 441.1 yl)-N-(3- 1H), 7.38 (d, J = 2.4 Hz, 1H), 3.65(s, 3H), 3.45 (M + H)⁺. methylimidazo[1,2- (p, J = 8.5 Hz, 1H), 2.79 (s,3H), 2.34-2.16 (m, a]pyridine-5- 2H), 2.16-1.88 (m, 3H), 1.88-1.72 (m,1H), sulfonyl)cyclopropane-1- 1.22 (q, J = 3.7 Hz, 2H), 0.82 (q, J = 3.8Hz, 2H). carboxamide Example 1-[2-methoxy-5- ¹H NMR (500 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-17 (trifluoromethyl)pyridin- δppm 8.50 (dd, J = 2.4, 1.1 Hz, 1H), 7.94 (dd, J = m/z 454.0 3-yl]-N-(1-7.8, 1.2 Hz, 1H), 7.92-7.87 (m, 1H), 7.81 (dd, (M + H)⁺.methyl-1H-indole-7- J = 7.7, 1.2 Hz, 1H), 7.44 (d, J = 3.2 Hz, 1H),sulfonyl)cyclopropane-1- 7.20 (t, J = 7.8 Hz, 1H), 6.69 (d, J = 3.2 Hz,1H), carboxamide 3.89 (s, 3H), 3.53 (s, 3H), 1.40 (q, J = 4.4 Hz, 2H),1.15 (q, J = 4.5 Hz, 2H). Example 1-[2-methoxy-5- ¹H NMR (500 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-18 (trifluoromethyl)pyridin- δppm 8.55-8.47 (m, 1H), 7.83 (ddt, J = 2.8, m/z 454.0 3-yl]-N-(1- 1.8,0.8 Hz, 1H), 7.81 (t, J = 0.8 Hz, 1H), 7.63 (M + H)⁺.methyl-1H-indole-4- (dd, J = 7.5, 0.9 Hz, 1H), 7.56 (d, J = 3.1 Hz,sulfonyl)cyclopropane-1- 1H), 7.34 (dd, J = 8.2, 7.5 Hz, 1H), 6.72 (dd,J = carboxamide 3.1, 0.9 Hz, 1H), 3.87 (s, 3H), 3.65 (s, 3H), 1.31 (q, J= 4.4 Hz, 2H), 1.18-0.98 (m, 2H). Example 1-[2-methoxy-5- ¹H NMR (500MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-19 (trifluoromethyl)pyridin-δ ppm 8.39 (dt, J = 2.4, 1.1 Hz, 1H), 8.07-7.97 m/z 455.0 3-yl]-N-(3-(m, 3H), 7.97-7.89 (m, 1H), 7.73 (d, J = 2.5 Hz, (M + H)⁺.methylimidazo[1,2- 1H), 3.75 (s, 3H), 2.79 (d, J = 1.1 Hz, 3H), 1.23a]pyridine-5- (q, J = 3.7 Hz, 2H), 0.87 (q, J = 3.8 Hz, 2H).sulfonyl)cyclopropane-1- carboxamide Example 1-[2-methoxy-5- ¹H NMR (400MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-20 (propan-2- δ ppm 7.20 (d,J = 2.2 Hz, 1H), 7.14 (dd, J = 8.4, m/z 443.1 yl)phenyl]-N- 2.2 Hz, 1H),7.08 (dd, J = 7.8, 1.4 Hz, 1H), 7.02 (M + H)⁺. (1,2,3,4- (t, J = 7.9 Hz,1H), 6.89 (d, J = 8.4 Hz, 1H), 6.69 tetrahydroquinoline-5- (dd, J = 7.9,1.4 Hz, 1H), 3.52 (s, 3H), 3.05 (t, J = sulfonyl)cyclobutane-1- 5.5 Hz,2H), 2.87 (hept, J = 6.8 Hz, 1H), carboxamide 2.67-2.57 (m, 2H), 2.46(t, J = 6.3 Hz, 2H), 2.43-2.20 (m, 2H), 1.87-1.66 (m, 2H), 1.66-1.47 (m,2H), 1.21 (d, J = 6.9 Hz, 6H). Example 1-(5-cyclopentyl-2- ¹H NMR (400MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-21 methoxyphenyl)- δ ppm7.21 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.4, 469.1 m/z N-(1,2,3,4- 2.2Hz, 1H), 7.08 (dd, J = 7.8, 1.4 Hz, 1H), 7.02 (M + H)⁺.tetrahydroquinoline-5- (t, J = 7.9 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H),6.70 sulfonyl)cyclobutane-1- (dd, J = 7.9, 1.4 Hz, 1H), 3.52 (s, 3H),3.05 (t, J = carboxamide 5.5 Hz, 2H), 3.01-2.85 (m, 1H), 2.67-2.57 (m,2H), 2.47 (t, J = 6.4 Hz, 2H), 2.27 (dt, J = 12.4, 8.7 Hz, 2H),2.10-1.94 (m, 2H), 1.94-1.30 (m, 10H). Example 1-[5-(butan-2-yl)-2- ¹HNMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-22 methoxyphenyl]-δ ppm 7.18-6.95 (m, 4H), 6.89 (d, J = 8.4 Hz, m/z 457.1 N-(1,2,3,4- 1H),6.68 (dd, J = 7.9, 1.5 Hz, 1H), 3.52 (s, 3H), (M + H)⁺.tetrahydroquinoline-5- 3.04 (t, J = 5.6 Hz, 2H), 2.75-2.54 (m, 4H),sulfonyl)cyclobutane-1- 2.45 (t, J = 6.8 Hz, 2H), 2.40-2.18 (m, 2H),carboxamide 1.85-1.67 (m, 2H), 1.63-1.47 (m, 4H), 1.19 (d, J = 6.9 Hz,3H), 0.79 (t, J = 7.3 Hz, 3H). Example 1-{2-methoxy-5- ¹H NMR (400 MHz,CDCl₃) δ ppm 9.28 (d, J = MS (APCI+) II-23 [(oxolan-3- 8.8 Hz, 1H), 9.22(bs, 1H), 8.63 (d, J = 8.6 Hz, m/z 469 yl)oxy]phenyl}-N- 1H), 8.59 (d, J= 7.4 Hz, 1H), 8.32 (bs, 1H), 8.01 (M + H)⁺. (quinoline-5- (t, J = 7.9Hz, 1H), 7.80 (dd, J = 3.8, 8.8 Hz, 1H), sulfonyl)cyclopropane-1-6.86-6.85 (m, 2H), 6.75 (t, J = 1.7 Hz, 1H), 4.88-4.83 carboxamide (m,1H), 4.05-3.97 (m, 3H), 3.93 (td, J = 4.3, 8.3 Hz, 1H), 3.65 (s, 3H),2.27-2.10 (m, 2H), 1.48 (q, J = 4.0 Hz, 2H), 1.02 (q, J = 3.9 Hz, 2H).Example 1-[2-chloro-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS(APCI+) II-24 (trifluoromethoxy) δ ppm 9.07 (dd, J = 4.3, 1.6 Hz, 1H),8.98 (dt, J = m/z 470.9 phenyl]-N- 8.8, 1.3 Hz, 1H), 8.42-8.28 (m, 2H),7.97 (dd, J = (M + H)⁺. (quinoline-5- 8.5, 7.5 Hz, 1H), 7.75 (dd, J =8.8, 4.2 Hz, 1H), sulfonyl)cyclopropane-1- 7.46 (d, J = 8.4 Hz, 1H),7.39-7.29 (m, 2H), carboxamide 1.62-1.43 (m, 2H), 1.23-1.06 (m, 2H).Example 1-[2-chloro-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS(APCI+) II-25 (trifluoromethoxy) δ ppm 7.57 (d, J = 8.5 Hz, 1H),7.43-7.30 (m, m/z 474.9 phenyl]-N- 2H), 7.12-6.96 (m, 2H), 6.73 (dd, J =7.7, 1.7 (M + H)⁺. (1,2,3,4- Hz, 1H), 3.18 (t, J = 5.5 Hz, 2H), 2.90 (t,J = 6.3 tetrahydroquinoline-5- Hz, 2H), 1.79 (p, J = 6.3 Hz, 2H), 1.61(q, J = 4.6 sulfonyl)cyclopropane-1- Hz, 2H), 1.22 (q, J = 4.7 Hz, 2H).carboxamide Example 1-[2-methoxy-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1(v/v)) MS (APCI+) II-26 (propan-2- δ ppm 7.17 (dd, J = 8.5, 2.3 Hz, 1H),7.14-6.96 m/z 429.1 yl)phenyl]-N- (m, 3H), 6.93 (d, J = 8.5 Hz, 1H),6.71 (dd, J = (M + H)⁺. (1,2,3,4- 6.3, 3.0 Hz, 1H), 3.70 (s, 3H),3.23-3.12 (m, tetrahydroquinoline-5- 2H), 2.91-2.75 (m, 3H), 1.76 (p, J= 6.2 Hz, sulfonyl)cyclopropane-1- 2H), 1.39 (q, J = 4.4 Hz, 2H), 1.18(d, J = 6.9 Hz, carboxamide 6H), 1.10-0.94 (m, 2H). Example1-[4-fluoro-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+)II-27 methoxy-5- δ ppm 7.10 (d, J = 8.8 Hz, 1H), 7.07-6.96 (m, m/z 447.0(propan-2- 2H), 6.80 (d, J = 12.6 Hz, 1H), 6.71 (dd, J = 5.9, (M + H)⁺.yl)phenyl]-N- 3.4 Hz, 1H), 3.70 (s, 3H), 3.24-3.13 (m, 2H), (1,2,3,4-3.13-2.98 (m, 1H), 2.85 (t, J = 6.3 Hz, 2H), tetrahydroquinoline-5- 1.77(p, J = 6.2 Hz, 2H), 1.38 (q, J = 4.3 Hz, 2H), sulfonyl)cyclopropane-1-1.20 (d, J = 6.9 Hz, 6H), 1.03 (q, J = 4.6 Hz, 2H). carboxamide Example1-[2-methoxy-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+)II-28 (trifluoromethyl)phenyl]- δ ppm 7.72-7.61 (m, 1H), 7.49 (d, J =2.3 Hz, m/z 455.0 N-(1,2,3,4- 1H), 7.17 (d, J = 8.6 Hz, 1H), 7.11-6.97(m, (M + H)⁺. tetrahydroquinoline-5- 2H), 6.73 (dd, J = 6.4, 2.9 Hz,1H), 3.78 (s, 3H), sulfonyl)cyclopropane-1- 3.18 (t, J = 5.5 Hz, 2H),2.86 (t, J = 6.4 Hz, 2H), carboxamide 1.77 (p, J = 6.3 Hz, 2H), 1.42 (q,J = 4.5 Hz, 2H), 1.18-0.99 (m, 2H). Example 1-(5-bromo-2- ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.49 (s, MS (ESI+) II-29 methoxyphenyl)- 1H), 8.58(d, J = 8.8 Hz, 1H), 8.29-8.16 (m, m/z 465 N-(2- 2H), 7.88 (dd, J = 8.4,7.5 Hz, 1H), 7.37 (d, J = (M + H)⁺. methylquinoline-5- 8.9 Hz, 1H), 7.21(d, J = 2.2 Hz, 1H), 7.09 (dd, J = sulfonyl)cyclobutane-1- 8.4, 2.2 Hz,1H), 6.59 (d, J = 8.3 Hz, 1H), 3.51 carboxamide (q, J = 8.8 Hz, 1H),3.17 (s, 1H), 3.12 (s, 3H), 2.69 (s, 3H), 2.45-2.35 (m, 2H), 2.31 (dtt,J = 10.6, 7.5, 2.5 Hz, 2H), 2.22-2.06 (m, 4H), 2.04-1.92 (m, 1H),1.90-1.77 (m, 1H), 1.73-1.50 (m, 2H). Example methyl 1-(4- ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.51 (s, MS (ESI+) II-30 methoxy-3-{1- 1H), 9.06(dd, J = 4.1, 1.6 Hz, 1H), 8.97 (dd, J = m/z 481 [(quinoline-5- 9.0, 1.4Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.31 (M + H)⁺. sulfonyl)car- (d, J =7.3 Hz, 1H), 7.99-7.86 (m, 1H), 7.72 (dd, bamoyl]cyclopropyl}phe- J =8.8, 4.2 Hz, 1H), 7.22 (dd, J = 8.4, 2.3 Hz, nyl)cyclopropane- 1H), 7.04(d, J = 2.4 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1-carboxylate 1H), 3.53 (s,3H), 3.33 (s, 3H), 1.44 (q, J = 3.9 Hz, 2H), 1.28 (q, J = 4.4 Hz, 2H),1.18 (q, J = 4.0 Hz, 2H), 0.96 (q, J = 4.5 Hz, 2H). Example methyl 4- ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.74 (s, MS (APCI+) II-31 methoxy-3-{1-1H), 9.06 (dd, J = 4.2, 1.6 Hz, 1H), 8.91 (dt, J = m/z 441[(quinoline-5- 8.7, 1.2 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.31 (M +H)⁺. sulfonyl)car- (d, J = 7.4 Hz, 1H), 7.99-7.88 (m, 2H), 7.70 (dd,bamoyl]cyclopropyl}benzoate J = 8.2, 3.3 Hz, 2H), 6.99 (d, J = 8.7 Hz,1H), 3.83 (s, 2H), 3.40 (s, 3H), 1.29 (q, J = 4.4 Hz, 2H), 0.96 (q, J =4.4 Hz, 2H). Example methyl 4- ¹H NMR (501 MHz, DMSO-d₆) δ ppm 11.64 (s,MS (APCI+) II-32 methoxy-3-{1- 1H), 8.60-8.45 (m, 1H), 8.28 (d, J = 8.2Hz, m/z 440 [(naphthalene-1- 1H), 8.24 (d, J = 7.4 Hz, 1H), 8.18-8.04(m, (M + H)⁺. sulfonyl)car- 1H), 7.92 (dd, J = 8.6, 2.2 Hz, 1H),7.75-7.59 bamoyl]cyclopropyl}benzoate (m, 4H), 6.97 (d, J = 8.6 Hz, 1H),3.82 (s, 3H), 3.17 (s, 3H), 1.29 (q, J = 4.3 Hz, 2H), 0.95 (m, 2H).Example 1-(5-cyclobutyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.64 (s, MS(ESI+) II-33 methoxy-4- 1H), 8.87 (d, J = 8.8 Hz, 1H), 8.28-8.19 (m, m/z466 methylpyridin-3- 2H), 7.91 (s, 1H), 7.89-7.84 (m, 1H), 7.62 (d, J =(M + H)⁺. yl)-N-(2- 8.9 Hz, 1H), 3.72 (s, 3H), 3.52-3.47 (m, 1H),methylquinoline-5- 2.73 (s, 3H), 2.31 (d, J = 14.4 Hz, 2H), 2.16 (s,sulfonyl)cyclopropane-1- 1H), 2.05-1.95 (m, 2H), 1.89 (s, 3H),carboxamide 1.84-1.73 (m, 1H), 1.45 (s, 2H), 0.95 (s, 2H). Example1-(5-bromo-2- ¹H NMR (501 MHz, chloroform-d) δ ppm 7.96 MS (APCI+) II-34methoxyphenyl)- (s, 1H), 7.50 (dd, J = 8.7, 2.5 Hz, 1H), 7.40-7.30 m/z465 N-(1-methyl-2,3- (m, 3H), 6.92 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 8.7(M + H)⁺. dihydro-1H- Hz, 1H), 3.85 (s, 3H), 3.58 (t, J = 8.2 Hz, 2H),indole-4- 3.40 (t, J = 8.2 Hz, 2H), 2.93 (s, 3H), 1.62 (q, J =sulfonyl)cyclopropane-1- 4.3 Hz, 2H), 1.08 (q, J = 4.3 Hz, 2H).carboxamide Example 1-(2-methoxy-6- ¹H NMR (501 MHz, chloroform-d) δ ppmMS (APCI+) II-35 methylphenyl)-N- 9.31-9.25 (m, 2H), 8.69 (d, J = 8.5Hz, 1H), 8.63 (dd, m/z 397 (quinoline-5- J = 7.5, 0.9 Hz, 1H), 8.32 (s,1H), 8.06 (dd, J = (M + H)⁺. sulfonyl)cyclopropane-1- 8.5, 7.5 Hz, 1H),7.83 (dd, J = 8.7, 4.5 Hz, 1H), carboxamide 7.33 (t, J = 8.0 Hz, 1H),6.87 (t, J = 8.4 Hz, 2H), 3.81 (s, 3H), 2.16 (s, 3H), 1.77-1.67 (m, 1H),1.58-1.50 (m, 1H), 1.21-1.12 (m, 1H), 1.01-0.93 (m, 1H). Example1-(6-methoxy-2,3- ¹H NMR (400 MHz, chloroform-d) δ ppm 8.07 MS (APCI+)II-36 dimethylphenyl)- (s, 1H), 7.57 (dd, J = 7.9, 1.2 Hz, 1H), 7.15(dd, J = m/z 415 N-(1,2,3,4- 8.3, 6.1 Hz, 2H), 6.84 (d, J = 8.1 Hz, 1H),6.74 (M + H)⁺. tetrahydroquinoline-5- (d, J = 8.4 Hz, 1H), 3.85 (s, 3H),3.34 (t, J = 5.6 sulfonyl)cyclopropane-1- Hz, 2H), 3.04-2.74 (m, 3H),2.26 (s, 3H), 2.24 carboxamide (s, 3H), 1.95 (hept, J = 5.8 Hz, 2H),1.85 (ddd, J = 10.0, 7.7, 3.9 Hz, 1H), 1.65 (ddd, J = 10.0, 7.5, 4.4 Hz,1H), 1.17 (ddd, J = 9.5, 7.7, 4.4 Hz, 1H), 0.96 (ddd, J = 9.5, 7.5, 3.9Hz, 1H). Example 1-(3-cyclopropyl- ¹H NMR (501 MHz, chloroform-d) δ ppm8.09 MS (APCI+) II-37 6-methoxy-2- (s, 1H), 7.60 (dd, J = 7.9, 1.1 Hz,1H), 7.18 (t, J = m/z 441 methylphenyl)-N- 8.0 Hz, 1H), 7.11 (dd, J =8.6, 0.8 Hz, 1H), 6.86 (M + H)⁺. (1,2,3,4- (dd, J = 8.1, 1.2 Hz, 1H),6.75 (d, J = 8.5 Hz, tetrahydroquinoline-5- 1H), 3.87 (s, 3H), 3.36 (t,J = 5.6 Hz, 2H), sulfonyl)cyclopropane-1- 3.01-2.87 (m, 3H), 2.45 (s,3H), 1.97 (h, J = 5.8 Hz, carboxamide 2H), 1.88 (ddd, J = 10.1, 7.7, 4.0Hz, 1H), 1.85-1.78 (m, 1H), 1.67 (ddd, J = 9.9, 7.6, 4.4 Hz, 1H), 1.19(ddd, J = 9.4, 7.7, 4.4 Hz, 1H), 1.04-0.87 (m, 3H), 0.66-0.57 (m, 2H).Example 1-(5-cyclobutyl-2- ¹H NMR (501 MHz, DMSO-d₆) δ ppm 11.12 (s, MS(ESI+) II-38 methoxy-4- 1H), 7.89 (s, 1H), 7.00 (s, 2H), 6.68 (s, 1H),6.14 m/z 456.2 methylpyridin-3- (s, 1H), 3.81 (s, 3H), 3.52 (q, J = 8.7Hz, 1H), (M + H)⁺. yl)-N-(1,2,3,4- 3.17 (s, 2H), 2.89 (s, 2H), 2.29 (d,J = 8.6 Hz, tetrahydroquinoline-5- 2H), 2.09 (s, 3H), 2.05-1.91 (m, 2H),sulfonyl)cyclopropane-1- 1.84-1.70 (m, 3H), 1.55 (s, 2H), 1.24 (s, 1H),carboxamide 0.91-0.72 (m, 2H). Example 1-(2,6-dimethoxy- ¹H NMR (400MHz, DMSO-d₆) δ 8.41 (d, J = 8.5 MS (ESI) II-39 3-methylphenyl)- Hz,1H), 8.32 (dd, J = 7.4, 1.5 Hz, 1H), 8.25 (dd, m/z 441 N-(2- J = 8.1,1.5 Hz, 1H), 7.68 (dd, J = 8.1, 7.4 Hz, (M + H)⁺. methylquinoline-8-1H), 7.61 (d, J = 8.5 Hz, 1H), 7.09-7.05 (m, 1H),sulfonyl)cyclopropane-1- 6.61 (d, J = 8.5 Hz, 1H), 3.50 (s, 3H), 3.01(s, carboxamide 3H), 2.67 (s, 3H), 2.04 (s, 3H), 1.67-1.63 (m, 2H),1.07-1.02 (m, 2H). Example 1-(5-cyclobutyl-2- ¹H NMR (501 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-40 methoxyphenyl)- δ ppm7.24-7.15 (m, 2H), 7.08-6.97 (m, 2H), m/z 441.0 N-(1-methyl-2,3- 6.92(d, J = 8.5 Hz, 1H), 6.71 (d, J = 8.0 Hz, 1H), (M + H)⁺. dihydro-1H-3.65 (s, 3H), 3.44 (p, J = 8.6 Hz, 1H), 3.36 (t, J = indole-4- 8.4 Hz,2H), 3.11 (t, J = 8.4 Hz, 2H), 2.75 (s, sulfonyl)cyclopropane-1- 3H),2.30-2.20 (m, 2H), 2.12-2.00 (m, 2H), carboxamide 2.00-1.87 (m, 1H),1.86-1.73 (m, 1H), 1.37-1.31 (m, 2H), 1.05-0.98 (m, 2H). Example1-(5-cyclobutyl-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+)II-41 methoxy-4- δ ppm 7.88 (d, J = 1.0 Hz, 1H), 7.80 (dd, J = 8.2, m/z454.0 methylpyridin-3- 0.9 Hz, 1H), 7.61 (dd, J = 7.5, 0.8 Hz, 1H), 7.55(M + H)⁺. yl)-N-(1-methyl- (d, J = 3.1 Hz, 1H), 7.31 (t, J = 7.9 Hz,1H), 6.78 1H-indole-4- (dd, J = 3.1, 0.9 Hz, 1H), 3.87 (s, 3H), 3.78 (s,sulfonyl)cyclopropane-1- 3H), 3.49 (q, J = 8.8 Hz, 1H), 2.34-2.25 (m,carboxamide 2H), 2.19-1.90 (m, 6H), 1.87-1.75 (m, 1H), 1.57-1.40 (m,2H), 1.09-0.81 (m, 2H). Example 1-(5-cyclobutyl-2- ¹H NMR (400 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-42 methoxy-4- δ ppm 7.96-7.84 (m,2H), 7.78 (dd, J = 7.8, 1.2 m/z 454.0 methylpyridin-3- Hz, 1H), 7.43 (d,J = 3.2 Hz, 1H), 7.17 (t, J = 7.7 (M + H)⁺. yl)-N-(1-methyl- Hz, 1H),6.67 (d, J = 3.2 Hz, 1H), 3.99 (s, 3H), 1H-indole-7- 3.78 (s, 3H),3.60-3.43 (m, 1H), 2.40-2.26 (m, sulfonyl)cyclopropane-1- 2H), 2.24-1.90(m, 6H), 1.85-1.74 (m, 1H), carboxamide 1.64-1.42 (m, 2H), 1.08-0.88 (m,2H). Example 1-(5-cyclobutyl-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1(v/v)) MS (APCI+) II-43 methoxy-4- δ ppm 8.31 (s, 1H), 8.15 (dd, J =7.9, 1.1 Hz, m/z 455.0 methylpyridin-3- 1H), 8.04 (dd, J = 7.5, 1.1 Hz,1H), 7.88 (d, J = (M + H)⁺. yl)-N-(1-methyl- 0.9 Hz, 1H), 7.32 (t, J =7.8 Hz, 1H), 4.22 (s, 1H-indazole-7- 3H), 3.74 (s, 3H), 3.62-3.43 (m,1H), sulfonyl)cyclopropane-1- 2.43-2.26 (m, 2H), 2.26-1.91 (m, 6H),1.91-1.71 carboxamide (m, 1H), 1.66-1.40 (m, 2H), 1.10-0.80 (m, 2H).Example 1-(5-cyclobutyl-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS(APCI+) II-44 methoxy-4- δ ppm 8.42 (d, J = 8.5 Hz, 1H), 8.30 (ddd, J =m/z 466.0 methylpyridin-3- 15.4, 7.8, 1.5 Hz, 2H), 7.85 (d, J = 1.0 Hz,1H), (M + H)⁺. yl)-N-(2- 7.77-7.65 (m, 1H), 7.62 (d, J = 8.5 Hz, 1H),methylquinoline-8- 3.63 (s, 3H), 3.48-3.31 (m, 1H), 2.66 (s, 3H),sulfonyl)cyclopropane-1- 2.29-2.17 (m, 2H), 2.12-1.83 (m, 3H),carboxamide 1.80-1.60 (m, 6H), 1.16-0.86 (m, 2H). Example1-(2-methoxy-6- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+)II-45 methylphenyl)-N- δ ppm 8.41 (d, J = 8.5 Hz, 1H), 8.35-8.25 (m, m/z411.1 (2-methylquinoline-8- 2H), 7.70 (t, J = 7.8 Hz, 1H), 7.60 (d, J =8.5 Hz, (M + H)⁺. sulfonyl)cyclopropane-1- 1H), 7.22 (t, J = 7.9 Hz,1H), 6.85 (d, J = 8.3 Hz, carboxamide 1H), 6.76 (d, J = 7.6 Hz, 1H),3.61 (s, 3H), 2.59 (s, 3H), 1.82 (s, 3H), 1.57-1.53 (m, 2H), 1.15-0.81(m, 2H). Example 1-(2-cyclobutyl-5- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1(v/v)) MS (APCI+) II-46 methoxyphenyl)- δ ppm 9.05 (dd, J = 4.2, 1.6 Hz,1H), 8.98 (dt, J = m/z 437.0 N-(quinoline-5- 8.8, 1.3 Hz, 1H), 8.40-8.29(m, 2H), 7.94 (dd, J = (M + H)⁺. sulfonyl)cyclopropane-1- 8.4, 7.4 Hz,1H), 7.72 (dd, J = 8.8, 4.2 Hz, 1H), carboxamide 7.16 (d, J = 8.5 Hz,1H), 6.84 (dd, J = 8.5, 2.8 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 3.73 (s,3H), 3.20-3.06 (m, 1H), 1.75-1.57 (m, 4H), 1.53-1.33 (m, 4H), 1.09-1.00(m, 2H). Example 1-(2-cyclobutyl-5- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1(v/v)) MS (APCI+) II-47 methoxyphenyl)- δ ppm 8.86 (d, J = 8.9 Hz, 1H),8.28-8.18 (m, m/z 451.0 N-(2- 2H), 7.88 (t, J = 7.9 Hz, 1H), 7.60 (d, J= 8.9 Hz, (M + H)⁺. methylquinoline-5- 1H), 7.15 (d, J = 8.5 Hz, 1H),6.84 (dd, J = 8.5, sulfonyl)cyclopropane-1- 2.7 Hz, 1H), 6.72 (d, J =2.8 Hz, 1H), 3.73 (s, carboxamide 3H), 3.14 (p, J = 8.8 Hz, 1H), 2.72(s, 3H), 1.77-1.59 (m, 4H), 1.56-1.33 (m, 4H), 1.07-0.95 (m, 2H).Example 1-[5- ¹H NMR (501 MHz, DMSO-d₆) δ ppm 11.57 (bs, MS (ESI+) II-48(hydroxymethyl)-2- 1H), 9.05 (dd, J = 4.2, 1.6 Hz, 1H), 8.98 (dt, J =m/z 413 methoxyphenyl]- 8.9, 1.1 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.31(M + H)⁺. N-(quinoline-5- (d, J = 7.4 Hz, 1H), 7.97-7.90 (m, 1H), 7.71(dd, sulfonyl)cyclopropane-1- J = 8.8, 4.1 Hz, 1H), 7.21 (dd, J = 8.4,2.1 Hz, carboxamide 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.82 (d, J = 8.4 Hz,1H), 5.03 (bs, 1H), 4.42 (s, 2H), 3.35 (s, 3H), 1.26 (q, J = 4.3 Hz,2H), 0.93 (q, J = 4.4 Hz, 2H). Example 1-[2-methoxy-5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.63 (s, MS (ESI+) II-49 (methoxymethyl)phe- 1H), 9.05(dd, J = 4.2, 1.6 Hz, 1H), 8.97 (dd, J = m/z 427 nyl]-N- 8.7, 1.1 Hz,1H), 8.32 (dd, J = 14.2, 7.9 Hz, 2H), (M + H)⁺. (quinoline-5- 7.93 (t, J= 8.0 Hz, 1H), 7.70 (dd, J = 8.8, 4.2 Hz, sulfonyl)cyclopropane-1- 1H),7.21 (dd, J = 8.3, 2.1 Hz, 1H), 7.06 (d, J = carboxamide 2.2 Hz, 1H),6.84 (d, J = 8.4 Hz, 1H), 4.31 (s, 2H), 3.36 (s, 3H), 3.28 (s, 3H),1.28-1.25 (m, 2H), 0.94 (m, 2H). Example 1-(2-methoxy-6- ¹H NMR (501MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-50 methylphenyl)-N-(2- δ ppm8.86 (dd, J = 8.9, 0.9 Hz, 1H), 8.28-8.18 m/z 411.1 methylquinoline-5-(m, 2H), 7.89 (dd, J = 8.4, 7.4 Hz, 1H), 7.63 (d, J = (M + H)⁺.sulfonyl)cyclopropane-1- 8.9 Hz, 1H), 7.24-7.09 (m, 1H), 6.85-6.71carboxamide (m, 2H), 3.62 (s, 3H), 2.73 (s, 3H), 1.97 (s, 3H), 1.52-1.45(m, 2H), 1.01-0.90 (m, 2H). Example 1-(6-methoxy-2,3- ¹H NMR (501 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-51 dimethylphenyl)- δ ppm 8.88(dd, J = 8.9, 0.9 Hz, 1H), 8.26 (td, J = m/z 425.0 N-(2- 7.7, 1.1 Hz,2H), 7.92 (dd, J = 8.4, 7.5 Hz, 1H), (M + H)⁺. methylquinoline-5- 7.66(d, J = 8.9 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), sulfonyl)cyclopropane-1-6.72 (d, J = 8.3 Hz, 1H), 3.59 (s, 4H), 2.75 (s, carboxamide 3H), 2.13(s, 3H), 1.89 (s, 3H), 1.52-1.45 (m, 2H), 1.02-0.83 (m, 2H). Example1-(3-cyclopropyl- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+)II-52 6-methoxy-2- δ ppm 8.86 (dd, J = 8.8, 0.9 Hz, 1H), 8.30-8.20 m/z451.0 methylphenyl)-N-(2- (m, 2H), 7.90 (dd, J = 8.4, 7.5 Hz, 1H), 7.63(d, J = (M + H)⁺. methylquinoline-5- 8.9 Hz, 1H), 6.97 (d, J = 8.4 Hz,1H), 6.72 (d, J = sulfonyl)cyclopropane-1- 8.5 Hz, 1H), 3.59 (s, 3H),2.73 (s, 3H), 2.06 (s, carboxamide 3H), 1.82-1.70 (m, 1H), 1.56-1.42 (m,2H), 1.04-0.78 (m, 4H), 0.55-0.47 (m, 2H). Example 1-(2-methoxy-6- ¹HNMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-53 methylphenyl)-N-δ ppm 7.21 (dd, J = 8.3, 7.5 Hz, 1H), 7.10-6.99 m/z 401.1 (1,2,3,4- (m,2H), 6.91-6.85 (m, 1H), 6.84-6.78 (m, (M + H)⁺. tetrahydroquinoline-5-1H), 6.73 (dd, J = 7.4, 1.9 Hz, 1H), 3.77 (s, 3H),sulfonyl)cyclopropane-1- 3.18 (t, J = 5.5 Hz, 2H), 2.85 (t, J = 6.4 Hz,2H), carboxamide 2.19 (s, 3H), 1.78 (p, J = 6.1 Hz, 2H), 1.66-1.47 (m,2H), 1.17-0.95 (m, 2H). Example 1-(3-chloro-2,6- ¹H NMR (501 MHz,DMSO-d₆) δ ppm 9.06 (dd, MS (ESI) II-54 dimethoxyphenyl)- J = 4.2, 1.6Hz, 1H), 9.01 (ddd, J = 8.7, 1.6, 1.0 m/z 447 N-(quinoline-5- Hz, 1H),8.35 (ddd, J = 8.4, 1.2, 1.0 Hz, 1H), (M + H)⁺. sulfonyl)cyclopropane-1-8.32 (dd, J = 7.5, 1.2 Hz, 1H), 7.94 (dd, J = 8.4, carboxamide 7.5 Hz,1H), 7.74 (dd, J = 8.7, 4.2 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 6.78 (d,J = 9.0 Hz, 1H), 3.57 (s, 3H), 3.45 (s, 3H), 1.49-1.46 (m, 2H),1.07-1.03 (m, 2H). Example 1-(5-methoxy-2- ¹H NMR (400 MHz, DMSO-d₆:D₂O= 9:1 (v/v)) MS (APCI+) II-55 methylphenyl)-N- δ ppm 9.02 (dd, J = 4.2,1.6 Hz, 1H), 8.93-8.88 m/z 397.0 (quinoline-5- (m, 1H), 8.38-8.27 (m,2H), 7.94 (dd, J = 8.5, (M + H)⁺. sulfonyl)cyclopropane-1- 7.4 Hz, 1H),7.66 (dd, J = 8.7, 4.2 Hz, 1H), 7.12 carboxamide (t, J = 7.9 Hz, 1H),6.82-6.74 (m, 1H), 6.66-6.61 (m, 1H), 6.61-6.55 (m, 1H), 3.65 (s, 3H),1.19-1.14 (m, 2H), 1.07-0.99 (m, 2H). Example 1-(3- ¹H NMR (400 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-56 methoxyphenyl)- δ ppm 9.06(dd, J = 4.2, 1.6 Hz, 1H), 8.99-8.91 m/z 383.0 N-(quinoline-5- (m, 1H),8.41-8.30 (m, 2H), 7.96 (dd, J = 8.4, (M + H)⁺. sulfonyl)cyclopropane-1-7.5 Hz, 1H), 7.72 (dd, J = 8.8, 4.2 Hz, 1H), carboxamide 7.03-6.95 (m,1H), 6.81-6.74 (m, 2H), 1.75 (s, 3H), 1.39-1.33 (m, 2H), 1.07-1.01 (m,2H). Example 1-(2-cyclopropyl- ¹H NMR (501 MHz, chloroform-d) δ ppm 9.05MS (APCI+) II-57 6-methoxyphenyl)- (dd, J = 4.2, 1.6 Hz, 1H), 8.78 (dt,J = 8.6, 1.2 m/z 423 N-(quinoline-5- Hz, 1H), 8.53 (dd, J = 7.5, 1.2 Hz,1H), 8.42 (d, J = (M + H)⁺. sulfonyl)cyclopropane-1- 8.4 Hz, 1H), 8.25(s, 1H), 7.87 (t, J = 8.0 Hz, carboxamide 1H), 7.53 (dd, J = 8.8, 4.2Hz, 1H), 7.09 (dd, J = 8.4, 2.4 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.82(d, J = 8.4 Hz, 1H), 3.58 (s, 3H), 1.87 (tt, J = 8.5, 5.1 Hz, 1H), 1.49(q, J = 4.1 Hz, 2H), 1.05-0.95 (m, 4H), 0.65 (dt, J = 6.5, 4.8 Hz, 2H).Example 1-[5-methoxy-2- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS(APCI+) II-58 (propan-2- δ ppm 9.11-8.96 (m, 2H), 8.36-8.20 (m, 2H), m/z417.0 yl)phenyl]-N- 7.89 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 8.7, 4.2 Hz,(M + H)⁺. (quinoline-5- 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.79 (dd, J =8.5, sulfonyl)cyclopropane-1- 2.7 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H),3.71 (s, carboxamide 3H), 2.74 (p, J = 6.8 Hz, 1H), 1.46-1.35 (m, 2H),1.07-0.93 (m, 2H), 0.78-0.59 (m, 6H). Example 1-(5-methoxy-2- ¹H NMR(400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-59 propylphenyl)-N- δppm 9.04-8.93 (m, 2H), 8.34-8.24 (m, 2H), m/z 417.0 (quinoline-5- 7.87(t, J = 7.9 Hz, 1H), 7.61 (dd, J = 8.7, 4.2 Hz, (M + H)⁺.sulfonyl)cyclopropane-1- 1H), 7.02-6.94 (m, 1H), 6.81-6.74 (m, 2H),carboxamide 3.74 (s, 3H), 2.18-2.10 (m, 2H), 1.38 (q, J = 4.2 Hz, 2H),1.32-1.14 (m, 2H), 0.98 (q, J = 4.2 Hz, 2H), 0.59 (t, J = 7.3 Hz, 3H).Example 1-(2-cyclopropyl- ¹H NMR (501 MHz, chloroform-d) δ ppm 8.66 MS(APCI+) II-60 6-methoxyphenyl)- (dd, J = 8.8, 0.8 Hz, 1H), 8.44 (dd, J =7.5, 1.2 m/z 437 N-(2- Hz, 1H), 8.32 (dt, J = 8.4, 1.1 Hz, 1H), 8.23 (s,(M + H)⁺. methylquinoline-5- 1H), 7.82 (dd, J = 8.5, 7.4 Hz, 1H), 7.40(d, J = sulfonyl)cyclopropane-1- 8.9 Hz, 1H), 7.10 (dd, J = 8.5, 2.3 Hz,1H), 6.94 carboxamide (d, J = 2.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H),3.62 (s, 3H), 2.81 (s, 3H), 1.87 (tt, J = 8.4, 5.1 Hz, 1H), 1.51-1.45(m, 2H), 1.07-0.94 (m, 4H), 0.69-0.61 (m, 2H). Example 1-(2,5- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.66 (bs, MS (ESI) II-61 dimethylphenyl)- 1H),9.06 (dd, J = 4.2, 1.6 Hz, 1H), 9.00-8.96 (m, m/z 381 N-(quinoline-5-1H), 8.37-8.33 (m, 1H), 8.32 (dd, J = 7.5, 1.2 Hz, (M + H)⁺.sulfonyl)cyclopropane-1- 1H), 7.93 (dd, J = 8.4, 7.5 Hz, 1H), 7.71 (dd,J = carboxamide 8.8, 4.2 Hz, 1H), 7.02-6.97 (m, 2H), 6.95 (d, J = 7.6Hz, 1H), 2.24 (s, 3H), 1.81 (s, 3H), 1.39-1.35 (m, 2H), 1.04-0.99 (m,2H). Example 1-(5-ethyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.54 (s, MS(APCI+) II-62 methoxyphenyl)- 1H), 9.05-9.02 (m, 1H), 8.99 (d, J = 8.8Hz, m/z 423 N-(quinoline-5- 1H), 8.36-8.24 (m, 2H), 7.95-7.88 (m, 1H),(M + H)⁺. sulfonyl)cyclopropane-1- 7.70 (s, 1H), 7.07 (d, J = 8.2 Hz,1H), 6.94 (d, J = carboxamide 2.0 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H),3.36 (s, 3H), 2.56-2.49 (m, 2H), 1.25-1.21 (m, 2H), 1.15 (t, J = 7.6 Hz,3H), 0.94-0.89 (m, 2H). Example 1-(2-methoxy-4- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.52 (s, MS (APCI+) II-63 methylphenyl)-N- 1H), 9.05(dd, J = 4.1, 1.6 Hz, 1H), 8.98 (dt, J = m/z 397 (quinoline-5- 8.7, 1.2Hz, 1H), 8.39-8.22 (m, 2H), 8.01-7.84 (M + H)⁺. sulfonyl)cyclopropane-1-(m, 1H), 7.70 (dd, J = 8.8, 4.2 Hz, 1H), 7.00 (d, J = carboxamide 8.0Hz, 1H), 6.73-6.65 (m, 2H), 3.37 (s, 3H), 2.30 (s, 3H), 1.22 (q, J = 4.2Hz, 2H), 0.90 (q, J = 4.3 Hz, 2H). Example 1-(2-methoxy-3- ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.76 (s, MS (APCI+) II-64 methylphenyl)-N- 1H),9.04 (dd, J = 4.2, 1.6 Hz, 1H), 9.02-8.97 m/z 397 (quinoline-5- (m, 1H),8.32 (t, J = 6.8 Hz, 2H), 7.92 (t, J = 8.0 (M + H)⁺.sulfonyl)cyclopropane-1- Hz, 1H), 7.68 (dd, J = 8.8, 4.2 Hz, 1H), 7.10(dd, carboxamide J = 7.2, 2.1 Hz, 1H), 7.01-6.88 (m, 2H), 3.20 (s, 3H),2.09 (s, 3H), 1.27 (q, J = 4.4 Hz, 2H), 1.05-0.96 (m, 2H). Example1-(4-cyclobutyl- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+)II-65 2,6- δ ppm 7.79 (d, J = 8.2 Hz, 1H), 7.59 (dd, J = m/z 468.9dimethoxyphenyl)- 18.1, 5.3 Hz, 2H), 7.30 (t, J = 7.9 Hz, 1H), (M + H)⁺.N-(1-methyl-1H- 6.80-6.73 (m, 1H), 6.46-6.36 (m, 2H), 3.86 (s, 3H),indole-4- 3.77 (s, 3H), 3.69 (s, 3H), 3.66-3.29 (m, 1H),sulfonyl)cyclopropane-1- 2.25-1.87 (m, 2H), 1.87-1.13 (m, 6H), 0.89 (s,carboxamide 2H). Example 1-(4-cyclobutyl- ¹H NMR (501 MHz, DMSO-d₆:D₂O =9:1 (v/v)) MS (APCI+) II-66 2,6- δ ppm 7.93-7.87 (m, 1H), 7.81-7.72 (m,2H), m/z 469.0 dimethoxyphenyl)- 7.45-7.38 (m, 1H), 7.18-7.12 (m, 1H),(M + H)⁺. N-(1-methyl-1H- 6.69-6.62 (m, 1H), 6.47 (d, J = 2.5 Hz, 2H),indole-7- 6.45-6.37 (m, 2H), 4.00 (s, 3H), 3.78 (s, 3H),sulfonyl)cyclopropane-1- 3.67-3.58 (m, 1H), 2.25-2.19 (m, 1H), 2.09-2.00carboxamide (m, 1H), 1.92-1.77 (m, 3H), 1.71-1.57 (m, 2H), 1.46-1.31 (m,1H), 0.98-0.87 (m, 2H). Example 1-(4-cyclobutyl- ¹H NMR (501 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-67 2,6- δ ppm 8.30 (s, 1H), 8.16(dd, J = 8.0, 1.1 Hz, m/z 470.0 dimethoxyphenyl)- 1H), 8.04 (dd, J =7.6, 1.1 Hz, 1H), 7.32 (t, J = (M + H)⁺. N-(1-methyl-1H- 7.8 Hz, 1H),6.47-6.36 (m, 2H), 4.25 (s, 3H), indazole-7- 3.78 (s, 3H), 3.69 (s, 3H),3.66-3.50 (m, 1H), sulfonyl)cyclopropane-1- 2.26-2.13 (m, 1H), 2.13-1.89(m, 1H), carboxamide 1.89-1.69 (m, 3H), 1.65-1.56 (m, 2H), 1.47-1.34 (m,1H), 1.02-0.91 (m, 2H). Example 1-(4-cyclobutyl- ¹H NMR (501 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-68 2,6- δ ppm 8.93 (d, J = 6.8Hz, 1H), 8.21 (s, 1H), m/z 456.0 dimethoxyphenyl)- 7.82-7.77 (m, 1H),7.06 (t, J = 7.1 Hz, 1H), 6.99 (s, (M + H)⁺. N-(pyrazolo[1,5- 1H),6.43-6.33 (m, 2H), 3.77 (s, 3H), 3.67 (s, a]pyridine-4- 3H), 3.53-3.42(m, 1H), 2.17-1.95 (m, 2H), sulfonyl)cyclopropane-1- 1.76-1.52 (m, 5H),1.42-1.36 (m, 1H), 0.91 (s, carboxamide 2H). Example 1-(4-cyclobutyl- ¹HNMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-69 2,6- δ ppm8.97-8.88 (m, 1H), 8.29-8.19 (m, 2H), m/z 481.0 dimethoxyphenyl)-7.95-7.85 (m, 1H), 7.66 (d, J = 8.9 Hz, 1H), (M + H)⁺. N-(2- 6.42-6.32(m, 2H), 3.77 (s, 3H), 3.64 (s, 3H), methylquinoline-5- 3.41 (p, J = 8.8Hz, 1H), 2.73 (s, 3H), 2.31-1.87 sulfonyl)cyclopropane-1- (m, 2H),1.70-1.43 (m, 5H), 1.40-1.30 (m, carboxamide 1H), 0.98-0.84 (m, 2H).Example N-(2- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-70aminoquinoline-5- δ ppm 8.93 (d, J = 9.8 Hz, 1H), 8.09-8.00 (m, m/z481.9 sulfonyl)-1-(4- 1H), 7.96-7.85 (m, 2H), 7.22 (d, J = 9.8 Hz, (M +H)⁺. cyclobutyl-2,6- 1H), 6.39 (s, 2H), 3.78 (s, 3H), 3.68 (s, 3H),dimethoxyphenyl) 3.57-3.45 (m, 1H), 2.23-1.95 (m, 2H), 1.84-1.50cyclopropane-1- (m, 5H), 1.45-1.28 (m, 1H), 1.00-0.85 (m, carboxamide2H). Example N-(2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.80 (d, J = MS(ESI+) II-71 aminoquinoline-5- 9.7 Hz, 1H), 8.38 (s, 1H), 7.95 (dd, J =7.0, 1.8 m/z 426 sulfonyl)-1-(5- Hz, 1H), 7.88-7.76 (m, 2H), 7.07 (dd, J= 8.8, (M + H)⁺. ethyl-2- 5.8 Hz, 2H), 6.93 (d, J = 2.3 Hz, 1H), 6.79(d, J = methoxyphenyl)cyclopropane-1- 8.3 Hz, 1H), 3.48 (s, 3H),2.55-2.49 (m, 2H), carboxamide 1.22 (q, J = 4.2 Hz, 2H), 1.13 (t, J =7.6 Hz, 3H), 0.92 (q, J = 4.3 Hz, 2H). Example 1-(5-ethyl-2- ¹H NMR (400MHz, DMSO-d₆) δ ppm 13.56 (s, MS (APCI+) II-72 methoxyphenyl)- 1H),11.22 (s, 1H), 8.32 (s, 1H), 7.85 (d, J = 8.4 m/z 399.9N-(1H-indazole-4- Hz, 1H), 7.64 (d, J = 7.3 Hz, 1H), 7.49 (t, J = 7.8(M + H)⁺. sulfonyl)cyclopropane-1- Hz, 1H), 7.07 (dd, J = 8.3, 2.2 Hz,1H), 6.93 (d, J = carboxamide 2.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H),3.43 (s, 3H), 2.55-2.48 (m, 2H), 1.24-1.18 (m, 2H), 1.13 (t, J = 7.6 Hz,3H), 0.96-0.88 (m, 2H). Example 1-(2-ethyl-6- ¹H NMR (400 MHz,chloroform-d) δ ppm 9.03 MS (APCI+) II-73 methoxyphenyl)- (dd, J = 4.2,1.6 Hz, 1H), 8.76 (ddd, J = 8.8, 1.6, m/z 423 N-(quinoline-5- 0.9 Hz,1H), 8.52 (dd, J = 7.4, 1.3 Hz, 1H), 8.41 (M + H)⁺.sulfonyl)cyclopropane-1- (dt, J = 8.5, 1.1 Hz, 1H), 8.24 (s, 1H), 7.86(dd, J = carboxamide 8.5, 7.5 Hz, 1H), 7.51 (dd, J = 8.8, 4.2 Hz, 1H),7.22 (dd, J = 8.4, 2.3 Hz, 1H), 7.03 (s, 1H), 6.84 (d, J = 8.4 Hz, 1H),3.58 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 1.52-1.45 (m, 2H), 1.28-1.21 (m,3H), 1.01 (q, J = 4.1 Hz, 2H). Example 1-(2-ethoxy-5- ¹H NMR (400 MHz,DMSO-d₆) δ ppm MS (APCI+) II-74 methylphenyl)-N- 13.66-13.50 (m, 1H),11.22 (s, 1H), 8.34 (s, 1H), 7.88 m/z 400 (1H-indazole-4- (d, J = 8.3Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.52 (M + H)⁺.sulfonyl)cyclopropane-1- (t, J = 7.9 Hz, 1H), 7.12-7.02 (m, 1H), 6.95(d, J = carboxamide 2.1 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 3.78 (q, J =6.9 Hz, 2H), 2.23 (s, 3H), 1.21 (q, J = 4.2 Hz, 2H), 0.94 (bt, J = 6.7Hz, 5H). Example N-(1H-indazole-4- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.55(s, MS (ESI+) II-75 sulfonyl)-1-{5- 1H), 11.17 (s, 1H), 8.36 (d, J = 1.0Hz, 1H), 7.84 m/z 414 methyl-2- (d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.2Hz, 1H), 7.47 (M + H)⁺. [(propan-2- (dd, J = 8.4, 7.3 Hz, 1H), 7.00 (dd,J = 8.3, 2.1 MS (ESI−) yl)oxy]phenyl}cyclopropane-1- Hz, 1H), 6.90 (d, J= 2.2 Hz, 1H), 6.77 (d, J = 8.3 m/z 412 carboxamide Hz, 1H), 4.41 (hept,J = 6.0 Hz, 1H), 2.18 (s, (M − H)⁻. 3H), 1.18 (q, J = 4.3 Hz, 2H), 0.99(d, J = 6.0 Hz, 6H), 0.89 (q, J = 4.4 Hz, 2H). Example 1-(4-cyclobutyl-¹H NMR (400 MHz, DMSO-d₆) δ ppm 13.53 (s, MS (APCI+) II-76 2,6- 1H),10.93 (s, 1H), 8.35 (s, 1H), 7.84 (d, J = 8.4 m/z 456 dimethoxyphenyl)-Hz, 1H), 7.63 (d, J = 7.3 Hz, 1H), 7.50-7.44 (m, (M + H)⁺.N-(1H-indazole-4- 1H), 6.39-6.32 (m, 2H), 3.74 (s, 3H), 3.64 (s,sulfonyl)cyclopropane-1- 3H), 3.37-3.27 (m, 1H), 2.18-2.06 (m, 1H),carboxamide 2.06-1.91 (m, 1H), 1.81-1.58 (m, 3H), 1.59-1.46 (m, 2H),1.36-1.25 (m, 1H), 0.92-0.77 (m, 2H). Example N-(1H-indazole-4- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 13.00 (s, MS (APCI+) II-77 sulfonyl)-1-(6- 1H),8.12 (s, 1H), 7.50 (s, 1H), 7.33 (d, J = 7.1 m/z 400 methoxy-2,3- Hz,1H), 7.29-7.22 (m, 1H), 7.18-7.02 (m, (M + H)⁺.dimethylphenyl)cyclopropane-1- 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.56 (d, J= 8.3 Hz, carboxamide 1H), 3.61 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H),1.29 (d, J = 3.7 Hz, 2H), 0.73 (dd, J = 9.6, 3.5 Hz, 1H), 0.46-0.35 (m,1H). Example 1-(3-cyclopropyl- ¹H NMR (501 MHz, DMSO-d₆) δ ppm 13.58 (s,MS (APCI+) II-78 6-methoxy-2- 1H), 11.06 (s, 1H), 8.33 (s, 1H), 7.87 (s,1H), m/z 426 methylphenyl)-N- 7.65 (s, 1H), 7.50 (d, J = 7.1 Hz, 1H),6.93 (d, J = (M + H)⁺. (1H-indazole-4- 8.5 Hz, 1H), 6.69 (d, J = 8.5 Hz,1H), 3.62 (s, sulfonyl)cyclopropane-1- 3H), 2.11 (s, 3H), 1.74 (tt, J =8.4, 5.4 Hz, 1H), carboxamide 1.49 (d, J = 27.2 Hz, 2H), 0.97 (s, 1H),0.82 (s, 3H), 0.49 (dd, J = 5.4, 2.5 Hz, 2H). Example N-(1H-indole-4- ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.57 (s, MS (APCI+) II-79 sulfonyl)-1-{5-1H), 10.77 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), m/z 413 methyl-2-7.59-7.50 (m, 2H), 7.18 (t, J = 7.8 Hz, 1H), (M + H)⁺. [(propan-2-7.03-6.96 (m, 1H), 6.89 (d, J = 2.2 Hz, 1H), 6.81 (ddd,yl)oxy]phenyl}cyclopropane-1- J = 3.0, 1.9, 0.9 Hz, 1H), 6.77 (d, J =8.3 Hz, carboxamide 1H), 4.42 (hept, J = 6.0 Hz, 1H), 2.17 (s, 3H), 1.19(q, J = 4.4 Hz, 2H), 1.02 (d, J = 6.0 Hz, 6H), 0.86 (q, J = 4.4 Hz, 2H).Example 1-(2,5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.60 (s, MS (APCI+)II-80 dimethylphenyl)- 1H), 11.02 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), m/z369 N-(1H-indole-4- 7.58-7.52 (m, 2H), 7.18 (t, J = 7.8 Hz, 1H), (M +H)⁺. sulfonyl)cyclopropane-1- 7.03-6.91 (m, 3H), 6.79 (d, J = 2.6 Hz,1H), 2.20 (s, carboxamide 3H), 1.89 (s, 3H), 1.41-1.31 (m, 2H),1.05-0.89 (m, 2H). Example 1-(2-cyclopropyl- ¹H NMR (400 MHz, DMSO-d₆) δppm 13.56 (s, MS (APCI+) II-81 6-methoxyphenyl)- 1H), 11.25 (s, 1H),8.31 (s, 1H), 7.85 (d, J = 8.3 m/z 425 N-(1H-indazole-4- Hz, 1H), 7.64(d, J = 7.3 Hz, 1H), 7.49 (dd, J = (M + H)⁺. sulfonyl)cyclopropane-1-8.4, 7.3 Hz, 1H), 6.92 (dd, J = 8.4, 2.3 Hz, 1H), carboxamide 6.82 (d, J= 2.3 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 3.41 (s, 3H), 1.81 (tt, J =8.4, 5.1 Hz, 1H), 1.19 (q, J = 4.3 Hz, 2H), 0.92 (q, J = 4.4 Hz, 2H),0.88-0.79 (m, 2H), 0.62-0.53 (m, 2H). Example N-(2- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.55 (s, (ESI+) II-82 aminoquinoline-5- 1H), 8.80 (d, J= 9.7 Hz, 1H), 8.31 (s, 2H), 7.95 m/z 482 sulfonyl)-1-{2- (dd, J = 7.2,1.6 Hz, 1H), 7.88-7.78 (m, 2H), (M + H)⁺. methoxy-5-[1- 7.15 (dd, J =8.5, 2.3 Hz, 1H), 7.08 (d, J = 9.7 (methoxymethyl)cyclopro- Hz, 1H),6.95 (d, J = 2.3 Hz, 1H), 6.78 (d, J = 8.5 pyl]phenyl}cyclopropane-1-Hz, 1H), 3.48 (s, 3H), 3.37 (s, 2H), 3.18 (s, 3H), carboxamide 1.25 (q,J = 4.2 Hz, 2H), 0.92 (q, J = 4.4 Hz, 2H), 0.75 (dt, J = 6.1, 1.8 Hz,4H). Example 1-(2-ethoxy-5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.40 (s, MS(ESI+) II-83 methylphenyl)-N-(2- 1H), 8.81 (d, J = 9.3 Hz, 1H),8.12-7.99 (m, m/z 441 methoxyquinoline-5- 2H), 7.79 (dd, J = 8.4, 7.5Hz, 1H), 7.14 (d, J = (M + H)⁺. sulfonyl)cyclopropane-1- 9.3 Hz, 1H),7.01 (dd, J = 8.4, 2.2 Hz, 1H), 6.91 carboxamide (d, J = 2.2 Hz, 1H),6.71 (d, J = 8.3 Hz, 1H), 3.99 (s, 3H), 3.65 (q, J = 6.9 Hz, 2H), 2.19(s, 3H), 1.19 (q, J = 4.3 Hz, 2H), 0.90 (t, J = 3.5 Hz, 2H), 0.81 (t, J= 6.9 Hz, 3H). Example 1-(2-ethoxy-5- : ¹H NMR (501 MHz, DMSO-d₆) δ ppm9.17 (s, MS (ESI+) II-84 methylphenyl)-N- 1H), 8.71 (d, J = 9.8 Hz, 1H),8.07 (d, J = 8.4 Hz, m/z 440 [2-(methylamino)quinoline-5- 1H), 7.97 (d,J = 7.6 Hz, 1H), 7.82 (t, J = 8.0 Hz, (M + H)⁺. sulfonyl]cyclopropane-1-1H), 7.09 (d, J = 9.8 Hz, 1H), 7.04 (dd, J = 8.3, carboxamide 2.2 Hz,1H), 6.93 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 3.78 (q, J =7.0 Hz, 2H), 3.07 (s, 3H), 2.21 (s, 3H), 1.21 (q, J = 4.2 Hz, 2H), 0.98(t, J = 6.9 Hz, 3H), 0.94 (q, J = 4.3 Hz, 2H). Example 1-(2-ethoxy-5- ¹HNMR (501 MHz, DMSO-d₆) δ ppm 11.59 (t, J = MS (ESI−) II-85methylphenyl)-N- 2.2 Hz, 1H), 10.79 (s, 1H), 7.68 (dd, J = 8.1, m/z 397(1H-indole-4- 1.0 Hz, 1H), 7.57 (dd, J = 7.5, 0.9 Hz, 1H), 7.54 (M −H)⁻. sulfonyl)cyclopropane-1- (t, J = 2.8 Hz, 1H), 7.20 (t, J = 7.8 Hz,1H), 7.03 carboxamide (dd, J = 8.3, 2.2 Hz, 1H), 6.92 (d, J = 2.2 Hz,1H), 6.80-6.76 (m, 2H), 3.78 (q, J = 6.9 Hz, 2H), 2.20 (s, 3H), 1.21 (q,J = 4.3 Hz, 2H), 0.96 (t, J = 6.9 Hz, 3H), 0.90 (q, J = 4.4 Hz, 2H).Example 1-[2-methoxy-5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.69 (s, MS(APCI+) II-86 (2,2,2-trifluoro-1- 1H), 9.06 (dd, J = 4.2, 1.6 Hz, 1H),8.98 (d, J = m/z 495 methoxyethyl)phe- 8.7 Hz, 1H), 8.34 (d, J = 8.5 Hz,1H), 8.30 (d, J = (M + H)⁺. nyl]-N-(quinoline-5- 7.4 Hz, 1H), 7.93 (t, J= 7.9 Hz, 1H), 7.72 (dd, J = sulfonyl)cyclopropane-1- 8.8, 4.2 Hz, 1H),7.33 (dd, J = 8.5, 2.1 Hz, 1H), carboxamide 7.16 (d, J = 2.1 Hz, 1H),6.94 (d, J = 8.5 Hz, 1H), 4.90 (q, J = 7.1 Hz, 1H), 3.38 (s, 3H), 3.33(s, 3H), 1.35 (bs, 2H), 0.93 (bs, 2H). Example 1-[2-methoxy-5- ¹H NMR(501 MHz, DMSO-d₆) δ ppm 11.58 (s, MS II-87 (1-methoxyethyl)phenyl]-1H), 9.06 (dd, J = 4.1, 1.6 Hz, 1H), 8.98 (d, J = (APCI+)N-(quinoline-5- 8.7 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.30 (d, J = m/z441 sulfonyl)cyclopropane-1- 7.4 Hz, 1H), 7.94 (t, J = 8.0 Hz, 1H), 7.71(dd, J = (M + H)⁺. carboxamide 8.7, 4.2 Hz, 1H), 7.18 (dd, J = 8.4, 2.2Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 4.23 (q, J= 6.4 Hz, 1H), 3.35 (s, 3H), 3.11 (s, 3H), 1.31 (d, J = 6.4 Hz, 3H),1.29 (m, 2H), 0.95 (bs, 2H). Example N-(1H-indole-4- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.60 (s, MS (ESI−) II-88 sulfonyl)-1-[2- 1H), 10.78 (s,1H), 7.67 (d, J = 8.1 Hz, 1H), 7.56- m/z 441 methoxy-5-(2- 7.52 (m, 2H),7.25-7.15 (m, 2H), 7.05 (d, J = (M − H)⁻. methoxypropan-2- 2.3 Hz, 1H),6.85 (d, J = 8.6 Hz, 1H), 6.79-6.74 yl)phenyl]cyclopropane-1- (m, 1H),3.50 (s, 3H), 2.91 (s, 3H), 1.38 (s, 6H), carboxamide 1.28 (q, J = 4.3Hz, 2H), 0.91 (q, J = 4.4 Hz, 2H). Example 1-[2-methoxy-5- ¹H NMR (400MHz, chloroform-d) δ ppm 9.03 MS (ESI−) II-89 (3-methyloxetan- (dd, J =4.1, 1.6 Hz, 1H), 8.79 (ddd, J = 8.7, 1.6, m/z 451 3-yl)phenyl]-N- 0.9Hz, 1H), 8.57-8.48 (m, 1H), 8.41 (d, J = 8.5 (M − H)⁻. (quinoline-5- Hz,1H), 8.26 (s, 1H), 7.86 (t, J = 8.0 Hz, 1H), sulfonyl)cyclopropane-1-7.52 (dd, J = 8.8, 4.2 Hz, 1H), 7.31-7.23 (m, carboxamide 1H), 7.07 (d,J = 2.4 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.89 (d, J = 5.6 Hz, 2H),4.65 (d, J = 5.6 Hz, 2H), 3.62 (s, 3H), 1.72 (s, 3H), 1.51 (q, J = 4.2Hz, 2H), 1.01 (q, J = 4.2 Hz, 2H). Example N-(2-aminoquinoline-5- ¹H NMR(500 MHz, DMSO-d₆) δ ppm 11.84 (s, MS (ESI−) II-90 sulfonyl)-1-{5- 1H),8.91 (d, J = 9.7 Hz, 1H), 8.63 (s, 2H), 8.03 m/z 452methyl-2-[(oxetan-3- (dd, J = 7.1, 1.7 Hz, 1H), 7.92-7.84 (m, 2H), (M −H)⁻. yl)oxy]phenyl}cyclopropane-1- 7.15 (d, J = 9.8 Hz, 1H), 7.06-6.97(m, 2H), carboxamide 6.45 (d, J = 8.1 Hz, 1H), 5.14-5.07 (m, 1H), 4.72(td, J = 6.3, 1.0 Hz, 2H), 4.26-4.19 (m, 2H), 2.24 (s, 3H), 1.30 (q, J =4.2 Hz, 2H), 1.02 (q, J = 4.3 Hz, 2H). Example N-(1H-indazole-4- ¹H NMR(400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-91 sulfonyl)-1-[2- δppm 8.28 (d, J = 1.0 Hz, 1H), 7.90 (dt, J = 8.4, m/z 445.1 methoxy-5-(2-1.0 Hz, 1H), 7.77-7.63 (m, 2H), 7.53 (dd, J = (M + H)⁺.methylpropoxy)pyridin-4- 8.4, 7.2 Hz, 1H), 6.63 (s, 1H), 3.78 (s, 3H),3.41 yl]cyclopropane- (d, J = 6.4 Hz, 2H), 1.40-1.22 (m, 3H), 1.02 (q,1-carboxamide J = 4.5 Hz, 2H), 0.65 (d, J = 6.7 Hz, 6H). Example1-(2-{[(2S)-1- ¹H NMR (501 MHz, chloroform-d) δ ppm 9.01 MS (ESI−) II-92methoxypropan-2- (dd, J = 4.2, 1.6 Hz, 1H), 8.78 (ddd, J = 8.8, 1.6, m/z453 yl]oxy}-5- 0.8 Hz, 1H), 8.72 (s, 1H), 8.51 (dd, J = 7.5, 1.2 (M −H)⁻. methylphenyl)-N- Hz, 1H), 8.40 (dt, J = 8.4, 1.1 Hz, 1H), 7.85 (dd,(quinoline-5- J = 8.4, 7.4 Hz, 1H), 7.46 (dd, J = 8.7, 4.1 Hz,sulfonyl)cyclopropane-1- 1H), 7.15 (ddd, J = 8.4, 2.2, 0.9 Hz, 1H),6.98-6.93 carboxamide (m, 1H), 6.91 (d, J = 8.4 Hz, 1H), 4.58 (td, J =6.3, 4.6 Hz, 1H), 3.48 (dd, J = 10.1, 6.1 Hz, 1H), 3.42-3.35 (m, 4H),2.28 (s, 3H), 1.54-1.49 (m, 1H), 1.46-1.41 (m, 1H), 1.26 (d, J = 6.3 Hz,3H), 1.06-0.98 (m, 2H). Example 1-[5-cyclopropyl- ¹H NMR (501 MHz,DMSO-d₆) δ ppm 11.63 (s, MS (ESI+) II-93 2-(2- 1H), 8.75 (d, J = 9.3 Hz,1H), 8.11-8.01 (m, m/z 496 methylpropoxy)pyridin- 2H), 7.85-7.75 (m,2H), 7.14 (dd, J = 5.9, 3.4 (M + H)⁺. 3-yl]-N-(2- Hz, 2H), 4.01 (s, 3H),3.54 (d, J = 6.6 Hz, 2H), methoxyquinoline-5- 1.84 (tt, J = 8.4, 5.1 Hz,1H), 1.29 (q, J = 4.3 Hz, sulfonyl)cyclopropane-1- 2H), 1.20 (hept, J =6.7 Hz, 1H), 0.98 (q, J = 4.4 carboxamide Hz, 2H), 0.93-0.84 (m, 2H),0.70-0.63 (m, 2H), 0.58 (d, J = 6.6 Hz, 6H). Example 1-[5-cyclobutyl-2-¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.62 (s, MS (ESI+) II-94(2-methylpropoxy)pyridin- 1H), 8.76 (dd, J = 9.3, 0.8 Hz, 1H), 8.10-8.00m/z 510 3-yl]-N-(2- (m, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7.78 (dd, J =(M + H)⁺. methoxyquinoline-5- 8.4, 7.5 Hz, 1H), 7.39 (d, J = 2.4 Hz,1H), 7.13 sulfonyl)cyclopropane-1- (d, J = 9.3 Hz, 1H), 4.00 (s, 3H),3.55 (d, J = 6.5 carboxamide Hz, 2H), 3.41 (p, J = 8.8 Hz, 1H), 2.22(qt, J = 8.0, 2.4 Hz, 2H), 2.14-2.02 (m, 2H), 1.98-1.88 (m, 1H),1.83-1.71 (m, 1H), 1.31 (q, J = 4.4 Hz, 2H), 1.20 (dt, J = 13.3, 6.6 Hz,1H), 0.99 (q, J = 4.5 Hz, 2H), 0.57 (d, J = 6.7 Hz, 6H). Example1-{5-cyclopropyl- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.60 (s, MS (ESI+)II-95 2-[(propan-2- 1H), 8.83 (d, J = 9.4 Hz, 1H), 8.11-7.98 (m, m/z 482yl)oxy]pyridin-3- 2H), 7.80 (d, J = 2.6 Hz, 1H), 7.77 (d, J = 8.3 Hz,(M + H)⁺. yl}-N-(2- 1H), 7.17 (d, J = 9.3 Hz, 1H), 7.09 (d, J = 2.4 Hz,methoxyquinoline-5- 1H), 4.95 (p, J = 6.1 Hz, 1H), 3.99 (s, 3H), 1.81sulfonyl)cyclopropane-1- (tt, J = 8.5, 5.2 Hz, 1H), 1.23 (q, J = 4.4 Hz,2H), carboxamide 0.98-0.94 (m, 2H), 0.93 (d, J = 6.2 Hz, 6H), 0.88-0.81(m, 2H), 0.65-0.59 (m, 2H). Example 1-[5-(2- ¹H NMR (500 MHz, DMSO-d₆) δppm 11.56 (s, MS (ESI−) II-96 ethoxypropan-2- 1H), 9.06 (dd, J = 4.2,1.6 Hz, 1H), 8.98 (dt, J = m/z 467 yl)-2- 8.7, 1.2 Hz, 1H), 8.35 (d, J =8.4 Hz, 1H), 8.31 (M − H)⁻. methoxyphenyl]- (dd, J = 7.4, 1.2 Hz, 1H),7.94 (dd, J = 8.4, 7.5 N-(quinoline-5- Hz, 1H), 7.72 (dd, J = 8.7, 4.2Hz, 1H), 7.25 (dd, sulfonyl)cyclopropane-1- J = 8.5, 2.3 Hz, 1H), 7.07(d, J = 2.4 Hz, 1H), carboxamide 6.82 (d, J = 8.6 Hz, 1H), 3.35 (s, 3H),3.12 (q, J = 7.0 Hz, 2H), 1.42 (s, 6H), 1.32 (q, J = 4.3 Hz, 2H), 1.02(t, J = 7.0 Hz, 3H), 0.95 (q, J = 4.5 Hz, 2H). Example 1-[2-ethoxy-5-(2-¹H NMR (501 MHz, DMSO-d₆) δ ppm 11.49 (s, MS (ESI−) II-97methoxypropan-2- 1H), 9.05 (dd, J = 4.1, 1.6 Hz, 1H), 8.97-8.92 m/z 467yl)phenyl]-N- (m, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.31 (d, J = 7.4 (M −H)⁻. (quinoline-5- Hz, 1H), 7.93 (t, J = 7.9 Hz, 1H), 7.68 (dd, J =sulfonyl)cyclopropane-1- 8.7, 4.2 Hz, 1H), 7.24-7.18 (m, 1H), 7.07 (d, J= carboxamide 2.3 Hz, 1H), 6.78 (d, J = 8.5 Hz, 1H), 3.64 (q, J = 7.0Hz, 2H), 2.95 (s, 3H), 1.42 (s, 6H), 1.33 (q, J = 4.4 Hz, 2H), 1.00-0.91(bs, 2H), 0.73 (t, J = 6.9 Hz, 3H). Example 1-[2- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.59 (s, MS (ESI−) II-98 (difluoromethoxy)- 1H), 9.03(dd, J = 4.2, 1.6 Hz, 1H), 8.98 (dt, J = m/z 445 5-ethylphenyl]-N- 8.8,1.3 Hz, 1H), 8.31 (dt, J = 8.6, 1.0 Hz, 1H), (M − H)⁻. (quinoline-5-8.28 (dd, J = 7.4, 1.2 Hz, 1H), 7.89 (dd, J = 8.5,sulfonyl)cyclopropane-1- 7.4 Hz, 1H), 7.70 (dd, J = 8.8, 4.2 Hz, 1H),7.14 carboxamide (dd, J = 8.3, 2.2 Hz, 1H), 7.07 (d, J = 2.2 Hz, 1H),6.93 (d, J = 8.3 Hz, 1H), 6.70 (t, J = 74.4 Hz, 1H), 2.53 (q, J = 7.6Hz, 2H), 1.36 (q, J = 4.5 Hz, 2H), 1.12 (t, J = 7.6 Hz, 3H), 1.05 (q, J= 4.6 Hz, 2H). Example 1-[2-methoxy-5- ¹H NMR (501 MHz, DMSO-d₆) δ ppm11.47 (s, MS (ESI−) II-99 (2-methoxypropan-2- 1H), 8.83 (d, J = 8.9 Hz,1H), 8.26-8.15 (m, m/z 467 yl)phenyl]-N-(2- 2H), 7.90-7.79 (m, 1H), 7.57(d, J = 8.9 Hz, (M − H)⁻. methylquinoline-5- 1H), 7.23 (dd, J = 8.5, 2.3Hz, 1H), 7.05 (d, J = sulfonyl)cyclopropane-1- 2.4 Hz, 1H), 6.81 (d, J =8.6 Hz, 1H), 3.36 (s, carboxamide 3H), 2.93 (s, 3H), 2.70 (s, 3H), 1.39(s, 6H), 1.29 (q, J = 4.3 Hz, 2H), 0.93 (q, J = 4.4 Hz, 2H). Example1-[2-methoxy-5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.49 (s, MS (ESI−)II-100 (1-methoxycyclobu- 1H), 8.81 (d, J = 8.8 Hz, 1H), 8.19 (td, J =7.6, m/z 479 tyl)phenyl]-N-(2- 1.1 Hz, 2H), 7.84 (dd, J = 8.4, 7.5 Hz,1H), 7.55 (M − H)⁻. methylquinoline-5- (d, J = 8.9 Hz, 1H), 7.24 (dd, J= 8.4, 2.3 Hz, sulfonyl)cyclopropane-1- 1H), 7.04 (d, J = 2.3 Hz, 1H),6.83 (d, J = 8.5 Hz, carboxamide 1H), 3.36 (s, 3H), 2.78 (s, 3H), 2.68(s, 3H), 2.35-2.16 (m, 4H), 1.81 (ddq, J = 10.9, 9.2, 4.8 Hz, 1H), 1.54(dp, J = 11.0, 8.4 Hz, 1H), 1.28 (q, J = 4.4 Hz, 2H), 0.92 (q, J = 4.5Hz, 2H). Example 1-[2- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS(APCI+) II-101 (difluoromethoxy)- δ ppm 8.92 (d, J = 8.9 Hz, 1H),8.28-8.20 (m, 447.2 m/z 5-methylphenyl]- 2H), 7.94-7.86 (m, 1H), 7.66(d, J = 9.0 Hz, (M + H)⁺. N-(2- 1H), 7.14 (dd, J = 8.4, 2.2 Hz, 1H),7.07 (d, J = methylquinoline-5- 2.4 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H),6.69 (t, J = sulfonyl)cyclopropane-1- 74.5 Hz, 1H), 2.73 (s, 3H), 2.25(s, 3H), 1.35 (q, carboxamide J = 4.5 Hz, 2H), 1.05 (q, J = 4.6 Hz, 2H).Example 1-[5-chloro-2- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS(APCI+) II-102 (difluoromethoxy) δ ppm 8.92 (d, J = 8.9 Hz, 1H),8.29-8.22 (m, 467.1 m/z phenyl]-N-(2- 2H), 7.96-7.89 (m, 1H), 7.68 (d, J= 8.9 Hz, (M + H)⁺. methylquinoline-5- 1H), 7.43 (dd, J = 8.7, 2.7 Hz,1H), 7.34 (d, J = sulfonyl)cyclopropane-1- 2.7 Hz, 1H), 7.10 (d, J = 8.7Hz, 1H), 6.79 (t, J = carboxamide 73.8 Hz, 1H), 2.75 (s, 3H), 1.35 (q, J= 4.5 Hz, 2H), 1.10 (q, J = 4.6 Hz, 2H). Example 1-[2- ¹H NMR (400 MHz,DMSO-d₆:D₂O = 9:1 (v/v)) MS (APCI+) II-103 (difluoromethoxy)- δ ppm 8.89(d, J = 8.9 Hz, 1H), 8.26-8.18 (m, 453.2 m/z 5-ethylphenyl]-N- 2H),7.92-7.84 (m, 1H), 7.63 (d, J = 9.0 Hz, (M + H)⁺. (2-methylquinoline-5-1H), 7.17 (dd, J = 8.4, 2.3 Hz, 1H), 7.08 (d, J =sulfonyl)cyclopropane-1- 2.2 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.68 (t,J = carboxamide 74.5 Hz, 1H), 2.72 (s, 3H), 2.61-2.52 (m, 2H), 1.37 (q,J = 4.5 Hz, 2H), 1.14 (t, J = 7.6 Hz, 3H), 1.06 (q, J = 4.6 Hz, 2H).Example 1-(2-{[(2S)-1- ¹H NMR (501 MHz, DMSO-d₆:D₂O = 9:1 (v/v)) MS(APCI+) II-104 methoxypropan-2- δ ppm 9.02 (d, J = 8.9 Hz, 1H),8.32-8.26 (m, 469.2 m/z yl]oxy}-5- 2H), 7.96 (dd, J = 8.5, 7.4 Hz, 1H),7.73 (d, J = (M + H)⁺. methylphenyl)-N- 9.0 Hz, 1H), 7.05 (dd, J = 8.4,2.2 Hz, 1H), 6.92 (2-methylquinoline-5- (d, J = 2.2 Hz, 1H), 6.83 (d, J= 8.4 Hz, 1H), 4.37 sulfonyl)cyclopropane-1- (h, J = 6.0 Hz, 1H), 3.16(s, 3H), 3.13-3.03 (m, carboxamide 2H), 2.77 (s, 3H), 2.21 (s, 3H),1.37-1.29 (m, 1H), 1.22-1.14 (m, 1H), 1.07-1.00 (m, 1H), 0.93-0.85 (m,4H). Example 1-[2-ethoxy-5-(1- ¹H NMR (400 MHz, DMSO-d₆:D₂O = 9:1 (v/v))MS (APCI+) II-105 methoxy-2- δ ppm 8.78 (d, J = 8.9 Hz, 1H), 8.26-8.19(m, m/z 497.2 methylpropan-2- 2H), 7.88 (dd, J = 8.3, 7.5 Hz, 1H), 7.57(d, J = (M + H)⁺. yl)phenyl]-N-(2- 8.9 Hz, 1H), 7.22 (dd, J = 8.6, 2.5Hz, 1H), 7.06 methylquinoline-5- (d, J = 2.4 Hz, 1H), 6.75 (d, J = 8.7Hz, 1H), 3.59 sulfonyl)cyclopropane-1- (q, J = 6.9 Hz, 2H), 3.31 (s,2H), 3.20 (s, 3H), carboxamide 2.70 (s, 3H), 1.29 (q, J = 4.5 Hz, 2H),1.21 (s, 6H), 0.94 (q, J = 4.4 Hz, 2H), 0.68 (t, J = 6.9 Hz, 3H).Example 1-[2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.71 (s, MS (ESI+) II-106(difluoromethoxy)-5-(2- 1H), 9.05 (dd, J = 4.2, 1.6 Hz, 1H), 8.99 (d, J= m/z 505 ethoxypropan-2- 8.5 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.29(dd, J = (M + H)⁺. yl)phenyl]-N- 7.5, 1.3 Hz, 1H), 7.91 (dd, J = 8.5,7.5 Hz, 1H), (quinoline-5- 7.71 (dd, J = 8.8, 4.2 Hz, 1H), 7.34 (dd, J =8.5, sulfonyl)cyclopropane-1- 2.4 Hz, 1H), 7.21 (d, J = 2.3 Hz, 1H),7.01 (d, J = carboxamide 8.7 Hz, 1H), 6.79 (t, J = 74.3 Hz, 1H), 3.14(q, J = 7.1 Hz, 2H), 1.46 (q, J = 4.5 Hz, 2H), 1.42 (s, 6H), 1.08 (q, J= 4.6 Hz, 2H), 1.03 (t, J = 7.0 Hz, 3H). Example 1-[2- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.70 (s, MS (ESI+) II-107 (difluoromethoxy)-5-(2- 1H),8.88 (d, J = 8.9 Hz, 1H), 8.24-8.18 (m, m/z 519 ethoxypropan-2- 2H),7.85 (dd, J = 8.4, 7.5 Hz, 1H), 7.61 (d, J = (M + H)⁺. yl)phenyl]-N-(2-8.9 Hz, 1H), 7.34 (dd, J = 8.5, 2.4 Hz, 1H), 7.21 methylquinoline-5- (d,J = 2.4 Hz, 1H), 7.01 (d, J = 8.6 Hz, 1H), 6.81 sulfonyl)cyclopropane-1-(t, J = 74.5 Hz, 1H), 3.14 (q, J = 7.0 Hz, 2H), carboxamide 2.71 (s,3H), 1.46 (q, J = 4.5 Hz, 2H), 1.42 (s, 6H), 1.07 (q, J = 4.8 Hz, 2H),1.03 (t, J = 7.0 Hz, 3H). Example 1-[2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm11.67 (s, MS (ESI−) II-108 (difluoromethoxy)-5-(2- 1H), 9.01 (dd, J =4.1, 1.6 Hz, 1H), 8.95 (dt, J = m/z 489 methoxypropan-2- 8.8, 1.2 Hz,1H), 8.32-8.27 (m, 1H), 8.25 (dd, J = (M − H)⁻. yl)phenyl]-N- 7.5, 1.3Hz, 1H), 7.87 (dd, J = 8.4, 7.4 Hz, 1H), (quinoline-5- 7.67 (dd, J =8.8, 4.2 Hz, 1H), 7.29 (dd, J = 8.5, sulfonyl)cyclopropane-1- 2.4 Hz,1H), 7.18 (d, J = 2.3 Hz, 1H), 6.98 (d, J = carboxamide 8.5 Hz, 1H),6.76 (t, J = 74.4 Hz, 1H), 2.94 (s, 3H), 1.42 (q, J = 4.6 Hz, 2H), 1.38(s, 6H), 1.05 (q, J = 4.7 Hz, 2H). Example 1-[2- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.65 (s, MS (ESI−) II-109 (difluoromethoxy)-5-(2- 1H),8.84 (d, J = 8.9 Hz, 1H), 8.17 (ddd, J = 10.2, m/z 479 methoxypropan-2-7.4, 1.1 Hz, 2H), 7.82 (dd, J = 8.4, 7.5 Hz, 1H), (M − H)⁻.yl)phenyl]-N-(2- 7.57 (d, J = 8.9 Hz, 1H), 7.29 (dd, J = 8.5, 2.3methylquinoline-5- Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 8.5sulfonyl)cyclopropane-1- Hz, 1H), 6.78 (t, J = 74.3 Hz, 1H), 2.94 (s,3H), carboxamide 2.68 (s, 3H), 1.41 (q, J = 4.7 Hz, 2H), 1.38 (s, 6H),1.14-0.91 (m, 2H). Example 1-[5-(1-ethoxy-2- ¹H NMR (400 MHz, DMSO-d₆) δppm 11.49 (s, MS (APCI+) II-110 methylpropan-2- 1H), 9.06 (dd, J = 4.1,1.6 Hz, 1H), 9.02-8.94 m/z 483 yl)-2- (m, 1H), 8.35 (d, J = 8.4 Hz, 1H),8.31 (dd, J = (M + H)⁺. methoxyphenyl]- 7.5, 1.2 Hz, 1H), 7.94 (dd, J =8.4, 7.5 Hz, 1H), N-(quinoline-5- 7.71 (dd, J = 8.8, 4.1 Hz, 1H), 7.24(dd, J = 8.6, sulfonyl)cyclopropane-1- 2.5 Hz, 1H), 7.08 (d, J = 2.4 Hz,1H), 6.77 (d, J = carboxamide 8.7 Hz, 1H), 3.40 (q, J = 7.0 Hz, 2H),3.33 (s, 3H), 1.31 (q, J = 4.3 Hz, 2H), 1.23 (s, 6H), 1.06 (t, J = 7.0Hz, 3H), 0.95 (q, J = 4.5 Hz, 2H). Example 1-[5-(1-ethoxy-2- ¹H NMR (400MHz, DMSO-d₆) δ ppm 11.43 (s, MS (APCI+) II-111 methylpropan-2- 1H),8.86 (d, J = 8.9 Hz, 1H), 8.26-8.18 (m, m/z 497 yl)-2- 2H), 7.91-7.84(m, 1H), 7.59 (d, J = 8.9 Hz, (M + H)⁺. methoxyphenyl]- 1H), 7.24 (dd, J= 8.6, 2.5 Hz, 1H), 7.08 (d, J = N-(2- 2.4 Hz, 1H), 6.77 (d, J = 8.7 Hz,1H), 3.39 (q, J = methylquinoline-5- 7.0 Hz, 2H), 3.36 (s, 3H), 2.72 (s,3H), 1.30 (q, J = sulfonyl)cyclopropane-1- 4.3 Hz, 2H), 1.22 (s, 6H),1.06 (t, J = 7.0 Hz, carboxamide 3H), 0.95 (q, J = 4.4 Hz, 2H). Example1-[5- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.70 (s, MS (APCI+) II-112(dimethylamino)- 1H), 9.02 (dd, J = 4.2, 1.6 Hz, 1H), 8.91-8.86 m/z 4692-(2-meth- (m, 1H), 8.34-8.27 (m, 2H), 7.91 (d, J = 8.0 Hz, (M + H)⁺.ylpropoxy)pyridin-3-yl]-N- 1H), 7.73 (d, J = 2.8 Hz, 1H), 7.65 (dd, J =8.8, (quinoline-5- 4.2 Hz, 1H), 7.33 (d, J = 2.9 Hz, 1H), 3.49 (d, J =sulfonyl)cyclopropane-1- 6.4 Hz, 2H), 2.91 (s, 6H), 1.32 (q, J = 4.4 Hz,carboxamide 2H), 1.19 (hept, J = 6.6 Hz, 1H), 1.01 (q, J = 4.5 Hz, 2H),0.52 (d, J = 6.6 Hz, 6H). Example 1-[2-methoxy-5- ¹H NMR (400 MHz,chloroform-d) δ ppm MS (APCI+) II-113 (1-methoxy-2- 8.69-8.63 (m, 1H),8.42 (dd, J = 7.5, 1.2 Hz, 1H), 8.39 m/z 483 methylpropan-2- (bs, 1H),8.29 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = (M + H)⁺. yl)phenyl]-N-(2- 8.5,7.4 Hz, 1H), 7.38 (dd, J = 8.8, 2.2 Hz, 2H), methylquinoline-5- 7.20 (d,J = 2.5 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), sulfonyl)cyclopropane-1- 3.62(s, 3H), 3.37 (s, 2H), 3.33 (s, 3H), 2.78 (s, carboxamide 3H), 1.48 (q,J = 4.1 Hz, 2H), 1.31 (s, 6H), 1.00 (q, J = 4.1 Hz, 2H). Example1-(5-ethyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.45 (s, MS (APCI+)II-115 {[(3S)-oxolan-3- 1H), 8.83 (d, J = 8.9 Hz, 1H), 8.21 (t, J = 7.2Hz, m/z 481 yl]oxy}phenyl)-N- 2H), 7.86 (t, J = 7.9 Hz, 1H), 7.56 (d, J= 8.9 Hz, (M + H)⁺. (2-methylquinoline-5- 1H), 7.06 (dd, J = 8.4, 2.2Hz, 1H), 6.98 (d, J = sulfonyl)cyclopropane-1- 2.2 Hz, 1H), 6.73 (d, J =8.3 Hz, 1H), 4.66 (td, J = carboxamide 4.7, 2.4 Hz, 1H), 3.65 (dd, J =9.9, 4.9 Hz, 1H), 3.56 (td, J = 8.1, 3.5 Hz, 1H), 3.44 (td, J = 8.6, 6.4Hz, 1H), 3.21 (dd, J = 9.8, 2.0 Hz, 1H), 2.71 (s, 3H), 2.53 (q, J = 7.6Hz, 1H), 1.86-1.72 (m, 1H), 1.40 (m, 1H), 1.26 (m, 2H), 1.16 (t, J = 7.6Hz, 3H), 0.92 (dd, J = 24.2, 8.0 Hz, 2H). Example 1-(5-methyl-2- ¹H NMR(400 MHz, DMSO-d₆) δ ppm 11.50 (s, MS (ESI+) II-117 {[(3S)-oxolan-3-1H), 9.02 (dd, J = 4.2, 1.6 Hz, 1H), 8.93 (dt, J = m/z 453yl]oxy}phenyl)-N- 8.8, 1.2 Hz, 1H), 8.35-8.26 (m, 2H), 7.91 (dd, J =(M + H)⁺. (quinoline-5- 8.4, 7.5 Hz, 1H), 7.66 (dd, J = 8.8, 4.2 Hz,1H), sulfonyl)cyclopropane-1- 7.01 (dd, J = 8.4, 2.1 Hz, 1H), 6.93 (d, J= 2.2 carboxamide Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 4.59 (ddt, J = 6.7,4.3, 1.9 Hz, 1H), 3.59 (dd, J = 9.9, 4.9 Hz, 1H), 3.52 (td, J = 8.2, 3.5Hz, 1H), 3.41 (td, J = 8.6, 6.3 Hz, 1H), 3.15 (dd, J = 9.9, 2.0 Hz, 1H),2.20 (s, 3H), 1.83-1.68 (m, 1H), 1.43-1.32 (m, 1H), 1.20 (qdd, J = 9.1,5.7, 3.0 Hz, 2H), 0.92 (ddd, J = 9.6, 5.7, 3.0 Hz, 1H), 0.85 (ddd, J =8.4, 5.7, 2.8 Hz, 1H).

TABLE 2 Example Name MS Example III-3 N-(benzenesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-4N-(3-cyanobenzene-1-sulfonyl)-4-(3- fluorophenyl)oxane-4-carboxamideExample III-5 N-(benzenesulfonyl)-1-(4-methoxyphenyl)cyclopropane-1-carboxamide Example III-6N-(benzenesulfonyl)-1-phenylcyclopropane-1- carboxamide Example III-7N-(benzenesulfonyl)-1-(4- chlorophenyl)cyclobutane-1-carboxamide ExampleIII-8 1-(2,4-dichlorophenyl)-N-(2,3-dihydro-1H-indene-5-sulfonyl)cyclopropane-1-carboxamide Example III-9N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-10N-(4-chlorobenzene-1-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide Example III-11 methyl5-{[1-(2,4- dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}-4-methoxythiophene-3- carboxylate Example III-121-(2,4-dichlorophcnyl)-N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)cyclopropane-1- carboxamide Example III-131-(2,4-dichlorophenyl)-N-[2- (trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide Example III-141-(2,4-dichlorophenyl)-N-[4- (trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide Example III-151-(2,4-dichlorophenyl)-N-[3- (trifluoromethyl)benzene-1-sulfonyl]cyclopropane-1-carboxamide Example III-161-(2,4-dichlorophenyl)-N-[4-(2-oxopyrrolidin-1-yl)benzene-1-sulfonyl]cyclopropane-1- carboxamide Example III-171-(2,4-dichlorophenyl)-N-[5-(1,2-oxazol-5-yl)thiophene-2-sulfonyl]cyclopropane-1- carboxamide Example III-181-(2,4-dichlorophenyl)-N-[4-(pyrrolidine-1-sulfonyl)benzene-1-sulfonyl]cyclopropane-1- carboxamide Example III-19N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)-N-methylcyclopropane-1- carboxamide Example III-201-(2,4-dichlorophenyl)-N-{4-[(propan-2-yl)oxy]benzene-1-sulfonyl}cyclopropane-1- carboxamide Example III-211-(2,4-dichlorophenyl)-N-[6-(morpholin-4-yl)pyridine-3-sulfonyl]cyclopropane-1- carboxamide Example III-22 benzyl4-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate Example III-23N-(2-chlorobenzene-1-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide Example III-241-(2,4-dichlorophenyl)-N-(4-methoxybenzene-1-sulfonyl)cyclopropane-1-carboxamide Example III-251-(2,4-dichlorophenyl)-N-(3,4-dimethoxybenzene-1-sulfonyl)cyclopropane-1- carboxamide Example III-26N-(3-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-271-(2,4-dichlorophenyl)-N-(naphthalene-2-sulfonyl)cyclopropane-1-carboxamide Example III-28N-(cyclopropanesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-29N-(benzenesulfonyl)-1-(4- methylphenyl)cyclopropane-1-carboxamideExample III-30 N-(benzenesulfonyl)-1-(2-fluorophenyl)cyclopropane-1-carboxamide Example III-31N-(benzenesulfonyl)-1-(4- fluorophenyl)cyclopropane-1-carboxamideExample III-32 N-(benzenesulfonyl)-1-(2-chlorophenyl)cyclopropane-1-carboxamide Example III-33N-(benzenesulfonyl)-1-(4- chlorophenyl)cyclopropane-1-carboxamideExample III-34 N-(benzenesulfonyl)-1-(3,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-351-(2-fluorophenyl)-N- (phenylmethanesulfonyl)cyclopropane-1- carboxamideExample III-36 1-(2,4-dichlorophenyl)-N-(1,1-dioxo-1λ⁶-thiolane-3-sulfonyl)cyclopropane-1- carboxamide Example III-371-(2,4-dichlorophenyl)-N-(4-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide Example III-38N-(2-cyano-5-fluorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-55N-(2-chloro-5-nitrobenzene-1-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide Example III-561-(3-chlorophenyl)-N-(6-ethoxy-1,3-benzothiazole-2-sulfonyl)cyclopropane-1- carboxamide Example III-571-(3-chlorophenyl)-N-(5-hydroxynaphthalene-1-sulfonyl)cyclopropane-1-carboxamide Example III-581-(3-chlorophenyl)-N-[5- (dimethylamino)naphthalene-1-sulfonyl]cyclopropane-1-carboxamide Example III-591-(2,4-dichlorophenyl)-N-(pyridine-3-sulfonyl)cyclopropane-1-carboxamide Example III-60N-(6-chloropyridine-3-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-61N-(benzenesulfonyl)-2,2-dimethyl-1- phenylcyclopropane-1-carboxamideExample III-62 methyl 5-{[1-(2,4- dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}furan-2-carboxylate Example III-63N-(5-bromothiophene-2-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-641-(2,4-dichlorophenyl)-N-[3- (trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide Example III-65 methyl 2-{[1-(2,4-dichlorophenyl)cyclopropane-1- carbonyl]sulfamoyl}benzoate ExampleIII-66 methyl 4-chloro-2-{[1-(2,4- dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoate Example III-672-{[1-(2,4-dichlorophenyl)cyclopropane-1- carbonyl]sulfamoyl(benzoicacid Example III-68 4-chloro-2-{[1-(2,4- dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoic acid Example III-69 benzyl4-{[1-(4-methylphenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate Example III-70 benzyl4-{[1-(3,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate Example III-71N-(benzenesulfonyl)-1-(3- bromophenyl)cyclopropane-1-carboxamide ExampleIII-72 1-(3-chlorophenyl)-N-[2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7- sulfonyl]cyclopropane-1-carboxamideExample III-73 1-(3-chlorophenyl)-N-[4-(1H-pyrazol-1-yl)benzene-1-sulfonyl]cyclopropane-1- carboxamide Example III-741-(3-chlorophenyl)-N-(3,4-dimethylbenzene-1-sulfonyl)cyclopropane-1-carboxamide Example III-751-(3-chlorophenyl)-N-(2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)cyclopropane-1-carboxamide Example III-76N-(1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide Example III-771-(2,4-dichlorophenyl)-N-(piperidine-4-sulfonyl)cyclopropane-1-carboxamide Example III-78N-(1-acetylpiperidine-4-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-791-(2,4-dichlorophenyl)-N-[1-(3- phenylpropanoyl)piperidine-4-sulfonyl]cyclopropane-1-carboxamide Example III-80 tert-butyl4-{[1-(2,4- dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate Example III-814-(3-methoxyphenyl)-N-(2-methylbenzene-1- sulfonyl)oxane-4-carboxamideExample III-82 N-(2-methylbenzene-1-sulfonyl)-4-(3-methylphenyl)oxane-4-carboxamide Example III-831-(3-chlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopentane-1-carboxamide Example III-841-(3-chlorophenyl)-N-(5-methylpyridine-2-sulfonyl)cyclopropane-1-carboxamide Example III-851-(2-methoxyphenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide Example III-861-(2H-1,3-benzodioxol-5-yl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1- carboxamide Example III-871-(2,4-dichlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide Example III-881-(4-chlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide Example III-89 tert-butyl4-(4-fluorophenyl)-4-[(naphthalene-1- MSsulfonyl)carbamoyl]piperidine-1-carboxylate (APCI+) m/z 413.0 (M + H −Boc)⁺. Example III-90 1-(3,4-dimethoxyphenyl)-N-(naphthalene-1- MSsulfonyl)cyclopentane-1-carboxamide (APCI+) m/z 440.0 (M + H)⁺. ExampleIII-91 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N- MS(naphthalene-1-sulfonyl)cyclopropane-1- (APCI+) m/z carboxamide 431.9(M + H)⁺. Example III-92 1-(3-bromophenyl)-N-(naphthalene-1- MS (ESI)sulfonyl)cyclopropane-1-carboxamide m/z 430/432 (M + H)⁺. Example III-931-(3-bromophenyl)-N-(quinoline-5- MS (ESI)sulfonyl)cyclopropane-1-carboxamide m/z 431/433 (M + H)⁺. Example III-944-(5-methoxy-2-methylphenyl)-1-methyl-N- MS (ESI+)(quinoline-5-sulfonyl)piperidine-4-carboxamide m/z 454 (M + H)⁺. ExampleIII-95 1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]- MSN-(pyrazolo[1,5-a]pyridine-4- (APCI+) m/zsulfonyl)cyclopropane-1-carboxamide 441.0 (M + H)⁺. Example III-961-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]- MSN-(1-methyl-1H-benzimidazole-7- (APCI+) m/zsulfonyl)cyclopropane-1-carboxamide 455.0 (M + H)⁺. Example III-971-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]- MSN-(1-methyl-1H-indazole-7- (APCI+) m/zsulfonyl)cyclopropane-1-carboxamide 455.0 (M + H)⁺. Example III-98N-(1H-indazole-4-sulfonyl)-1-[2-methoxy-5- MS(trifluoromethyl)pyridin-3-yl]cyclopropane-1- (APCI+) m/z carboxamide441.0 (M + H)⁺. Example III-991-(5-cyano-2-methoxyphenyl)-N-(quinoline-5- MSsulfonyl)cyclopropane-1-carboxamide (APCI+) m/z 408.1 (M + H)⁺. ExampleIII-100 1-(5-cyano-2-methoxyphenyl)-N-(1,2,3,4- MStetrahydroquinoline-5-sulfonyl)cyclopropane-1- (APCI+) m/z carboxamide412.1 (M + H)⁺. Example III-101 1-[5-(bicyclo[1.1.1]pentan-1-yl)-2- MSmethoxyphenyl]-N-(1,2,3,4- (APCI+) m/ztetrahydroquinoline-5-sulfonyl)cyclopropane-1- 453.0 carboxamide (M +H)⁺. Example III-102 1-(2-methoxy-6-methylphenyl)-N-(1-methyl- MS1H-indole-4-sulfonyl)cyclopropane-1- (APCI+) m/z carboxamide 399.1 (M +H)⁺. Example III-103 1-(3,5-dichloro-2,6-dimethoxyphenyl)-N- MS (ESI)(quinoline-5-sulfonyl)cyclopropane-1- m/z 481/483 carboxamide (M + H)⁺.Example III-104 1-(2,4-dichlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1- carboxamide Example III-1051-(2,4-dichlorophenyl)-N- (trifluoromethanesulfonyl)cyclopropane-1-carboxamide Example III-106 1-(2,4-dichlorophenyl)-N-(2,2,2-trifluoroethanesulfonyl)cyclopropane-1- carboxamide Example III-1071-(2,4-dichlorophenyl)-N-(propane-1- sulfonyl)cyclopropane-1-carboxamideExample III-108 N-(3-chloropropane-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide Example III-1091-(3-chlorophenyl)-N- (phenylmethanesulfonyl)cyclopropane-1- carboxamideExample III-110 1-(2,4-dichlorophenyl)-N-(propane-2-sulfonyl)cyclopropane-1-carboxamide Example III-1111-(4-methylphenyl)-N- (phenylmethanesulfonyl)cyclopropane-1- carboxamideExample III-112 1-(4-fluorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1- carboxamide Example III-1131-(2-chlorophenyl)-N- (phenylmethanesulfonyl)cyclopropane-1- carboxamideExample III-114 1-(4-chlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1- carboxamide Example III-1151-(3,4-dichlorophenyl)-N- (phenylmethanesulfonyl)cyclopropane-1-carboxamide Example III-116 N-(pentane-3-sulfonyl)-1-phenylcyclopropane-1-carboxamide Example III-119 4-(3-methoxyphenyl)-N-(propane-1-sulfonyl)oxane-4-carboxamide Example III-1204-(3-methylphenyl)-N-(propane-1- sulfonyl)oxane-4-carboxamide ExampleIII-121 1-(3,4-dimethoxyphenyl)-N-(naphthalene-1- MSsulfonyl)cyclobutane-1-carboxamide (APCI+) m/z 426.0 (M + H)⁺. ExampleIII-122 1-[2-methoxy-6-(1-methyl-1H-pyrazol-4- MSyl)phenyl]-N-(quinoline-5- (APCI+) m/zsulfonyl)cyclopropane-1-carboxamide 463 (M + H)⁺. Example III-1231-(4-cyclobutyl-2,6-dimethoxyphenyl)-N-(1- MS methyl-1H-benzimidazole-7-(APCI+) m/z sulfonyl)cyclopropane-1-carboxamide 470.0 (M + H)⁺. ExampleIII-124 1-(3-methoxy-6-methylpyridin-2-yl)-N- MS(quinoline-5-sulfonyl)cyclopropane-1- (APCI+) m/z carboxamide 398 (M +H)⁺. Example III-125 1-(3-methoxy-6-methylpyridin-2-yl)-N- MS(naphthalene-1-sulfonyl)cyclopropane-1- (APCI+) m/z carboxamide 397 (M +H)⁺. Example III-126 1-(3-methoxy-6-methylpyridin-2-yl)-N-(2- MSmethylquinoline-5-sulfonyl)cyclopropane-1- (APCI+) m/z carboxamide 412(M + H)⁺. Example III-127 1-(2,5-dimethylphenyl)-N-(1H-indazole-4- MSsulfonyl)cyclopropane-1-carboxamide (APCI+) m/z 370 (M + H)⁺. ExampleIII-128 1-[2-methoxy-5-(3-methoxyoxetan-3- MS yl)phenyl]-N-(quinoline-5-(APCI+) m/z sulfonyl)cyclopropane-1-carboxamide 469 (M + H)⁺. ExampleIII-129 1-{2-methoxy-5-[(3-²H)oxetan-3-yl]phenyl}-N- MS (ESI−)(quinoline-5-sulfonyl)cyclopropane-1- m/z 438 carboxamide (M − H)⁻.Example III-130 N-(1H-indazole-4-sulfonyl)-1-[5-methyl-2-(2- MSmethylpropoxy)pyridin-3-yl]cyclopropane-1- (APCI+) m/z carboxamide 429.1(M + H)⁺. Example III-131 N-(1H-indazole-4-sulfonyl)-1-{5-methyl-2- MS[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1- (APCI+) m/z carboxamide415.1 (M + H)⁺. Example III-1321-(2-ethyl-6-methoxyphenyl)-N-(1H-indazole- MS (ESI+)4-sulfonyl)cyclopropane-1-carboxamide m/z 400 (M + H)⁺. Example III-1331-(2-ethyl-6-methoxyphenyl)-N-(2- MSmethylquinoline-5-sulfonyl)cyclopropane-1- (APCI+) m/z carboxamide 425(M + H)⁺. Example III-134 N-[2-(dimethylamino)quinoline-5-sulfonyl]-1-MS (ESI+) (2-ethoxy-5-methylphenyl)cyclopropane-1- m/z 454 carboxamide(M + H)⁺.

Example GI-11-{5-bromo-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-bromo-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (30 mg,0.10 mmol) in anhydrous dichloromethane (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (43 mg, 0.20 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (15 mg, 0.12 mmol) were added and the mixture was stirred atambient temperature for 30 minutes. Quinoline-5-sulfonamide (CAS#415913-05-2) (23 mg, 0.11 mmol) was added and the reaction mixture wasstirred at ambient temperature for 2.5 hours. The reaction mixture wastreated with water. The organic layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm9.19-9.12 (m, 1H), 8.88 (dd, J=4.2, 1.7 Hz, 1H), 8.29 (dd, J=7.3, 1.2Hz, 1H), 8.12 (dt, J=8.5, 1.1 Hz, 1H), 7.95 (d, J=2.6 Hz, 1H), 7.78 (dd,J=8.5, 7.3 Hz, 1H), 7.58 (dd, J=8.8, 4.3 Hz, 1H), 7.55 (d, J=2.6 Hz,1H), 4.97-4.87 (m, 2H), 1.44 (q, J=4.0 Hz, 2H), 0.91 (d, J=6.2 Hz, 6H),0.81 (q, J=4.0 Hz, 2H). MS (ESI+) m/z 492 (M+2H)⁺.

Example GI-21-{5-bromo-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-bromo-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (30 mg,0.10 mmol) in anhydrous dichloromethane (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (43 mg, 0.20 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (15 mg, 0.12 mmol) were added and the mixture was stirred atambient temperature for 30 minutes.1,2,3,4-Tetrahydroquinoline-5-sulfonamide (CAS #1155515-51-7) (23 mg,0.11 mmol) was added and the reaction mixture was stirred at ambienttemperature for 2.5 hours. The reaction mixture was treated with water.The organic layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.98 (s, 1H), 7.60 (s, 1H), 7.24(dd, J=7.8, 1.2 Hz, 1H), 6.90 (t, J=8.0 Hz, 1H), 6.58 (d, J=7.9 Hz, 1H),5.17 (p, J=6.1 Hz, 1H), 3.27-3.19 (m, 2H), 3.11-2.98 (q, J=7.2 Hz, 6H),1.86 (p, J=6.3 Hz, 2H), 1.49 (q, J=4.0 Hz, 2H), 1.26 (d, J=6.1 Hz, 6H),0.92-0.80 (m, 2H). MS (ESI+) m/z 496 (M+2H)⁺.

Example GI-31-(5-chloro-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(5-chloro-2-methoxy-4-pyridyl)cyclopropanecarboxylic acid (90 mg,0.395 mmol) in anhydrous dichloromethane (8 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (151 mg, 0.79 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (48 mg, 0.395 mmol) were added, followed bynaphthalene-1-sulfonamide (CAS #606-25-7)(74 mg, 0.356 mmol). Thereaction mixture was stirred at ambient temperature for 4 hours. Thereaction mixture was quenched with saturated aqueous NaHCO₃ solution,and the organic layer was separated on a phase separator andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% formic acid/acetonitrile+0.1% formic acid to give the compound.¹H NMR (400 MHz, chloroform-d) δ ppm 8.49 (dd, J=7.5, 1.3 Hz, 1H),8.39-8.33 (m, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.12 (s, 1H), 7.97 (dd,J=6.9, 2.4 Hz, 1H), 7.69-7.57 (m, 3H), 6.71 (s, 1H), 3.96 (s, 3H), 1.60(q, J=4.3 Hz, 2H), 1.06 (q, J=4.3 Hz, 2H). MS (ESI+) m/z 417 (M+H)⁺.

Example GI-41-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (92 mg, 0.48 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.26 mmol) in anhydrous dichloromethane (2 mL), amixture of1-[2-isopropyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylic acidand 1-[2-propyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylicacid (66 mg, 0.24 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(50 mg, 0.24 mmol) was added and the reaction mixture was stirred atreflux for 2 hours. The reaction mixture was quenched with water and theorganic layer was separated on phase separator and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound. ¹H NMR(400 MHz, methanol-d₄) δ ppm 9.05-8.97 (m, 2H), 8.49 (dd, J=7.5, 1.2 Hz,1H), 8.37 (dt, J=8.5, 1.1 Hz, 1H), 7.95 (dd, J=8.5, 7.4 Hz, 1H), 7.83(d, J=8.0 Hz, 1H), 7.72-7.62 (m, 1H), 7.61-7.51 (m, 1H), 2.41-2.33 (m,2H), 1.61-1.54 (m, 2H), 1.54-1.40 (m, 2H), 1.18 (q, J=4.4 Hz, 2H), 0.66(t, J=7.4 Hz, 3H). MS (ESI+) m/z 464 (M+H)⁺.

Example GI-51-[2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (32 mg, 0.16 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (11 mg, 0.09 mmol) in anhydrous dichloromethane (1 mL),1-[2-cyclopropyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylicacid (22 mg, 0.08 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(17 mg, 0.08 mmol) was added and the reaction mixture was stirred atreflux for 2 hours. The reaction mixture was quenched with water and theorganic layer was separated on phase separator and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5m OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.10 (ddd, J=8.7, 1.7, 0.9 Hz, 1H),8.87 (dd, J=4.2, 1.7 Hz, 1H), 8.29 (dd, J=7.3, 1.2 Hz, 1H), 8.13 (dt,J=8.5, 1.1 Hz, 1H), 7.79 (dd, J=8.5, 7.3 Hz, 1H), 7.67-7.60 (m, 1H),7.51 (dd, J=8.7, 4.3 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 5.50 (s, 1H), 2.01(tt, J=8.1, 4.9 Hz, 1H), 1.58 (d, J=3.4 Hz, 2H), 0.97 (d, J=3.3 Hz, 2H),0.79 (dd, J=4.8, 3.2 Hz, 2H), 0.50 (dq, J=6.6, 3.2 Hz, 2H). MS (ESI+)m/z 462 (M+H)⁺.

Example GI-61-[2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (32 mg, 0.16 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (11 mg, 0.09 mmol) in anhydrous dichloromethane (1 mL),1-[2-cyclopropyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylicacid (22 mg, 0.08 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1,2,3,4-Tetrahydroquinoline-5-sulfonamide(CAS #1155515-51-7) (17 mg, 0.08 mmol) was added and the reactionmixture was stirred at reflux for 2 hours. The reaction mixture wasquenched with water and the organic layer was separated on phaseseparator and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.83 (dd,J=8.0, 0.8 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.23 (dd, J=7.8, 1.2 Hz,1H), 7.01 (t, J=8.0 Hz, 1H), 6.72 (dd, J=8.1, 1.2 Hz, 1H), 3.25-3.18 (m,2H), 2.85 (t, J=6.4 Hz, 2H), 2.18 (tt, J=8.0, 4.7 Hz, 1H), 2.03 (s, 2H),1.83-1.74 (m, 2H), 1.74-1.60 (m, 2H), 1.26 (q, J=4.3 Hz, 2H), 1.06 (dt,J=4.7, 3.1 Hz, 2H), 0.97-0.85 (m, 2H). MS (ESI+) m/z 466 (M+H)⁺.

Example GI-71-[2-(propan-2-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (92 mg, 0.48 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.26 mmol) in anhydrous dichloromethane (2 mL), amixture of1-[2-isopropyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylic acidand 1-[2-propyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylicacid (66 mg, 0.24 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(50 mg, 0.24 mmol) was added and the reaction mixture was stirred atreflux for 2 hours. The reaction mixture was quenched with water and theorganic layer was separated on phase separator and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5m OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound ¹H NMR(400 MHz, methanol-d₄) δ ppm 9.10 (dt, J=8.7, 1.3 Hz, 1H), 9.00 (dd,J=4.3, 1.6 Hz, 1H), 8.47 (dd, J=7.5, 1.2 Hz, 1H), 8.34 (dt, J=8.5, 1.1Hz, 1H), 7.93 (dd, J=8.5, 7.4 Hz, 1H), 7.84-7.74 (m, 1H), 7.68 (dd,J=8.8, 4.3 Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 3.36 (s, 1H), 3.08 (h, J=6.7Hz, 1H), 1.59 (q, J=4.4 Hz, 2H), 1.20 (q, J=4.4 Hz, 2H), 0.95 (d, J=6.6Hz, 6H). MS (ESI+) m/z 464 (M+H)⁺.

Example GI-81-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (92 mg, 0.48 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.26 mmol) in anhydrous dichloromethane (2 mL), amixture of1-[2-isopropyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylic acidand 1-[2-propyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylicacid (66 mg, 0.24 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1,2,3,4-Tetrahydroquinoline-5-sulfonamide(CAS #1155515-51-7) (51 mg, 0.24 mmol) was added and the reactionmixture was stirred at reflux for 2 hours. The reaction mixture wasquenched with water and the organic layer was separated on phaseseparator and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.94-7.88(m, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.24 (dd, J=7.8, 1.2 Hz, 1H), 7.02 (t,J=8.0 Hz, 1H), 6.76-6.70 (m, 1H), 3.25-3.19 (m, 2H), 2.82 (t, J=6.4 Hz,2H), 2.71-2.59 (m, 2H), 1.84-1.74 (m, 2H), 1.73-1.61 (m, 4H), 1.22 (q,J=4.5 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H). MS (ESI+) m/z 468 (M+H)⁺.

Example GI-91-[2-(propan-2-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (92 mg, 0.48 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.26 mmol) in anhydrous dichloromethane (2 mL), anda mixture of1-[2-isopropyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylic acidand 1-[2-propyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylicacid (66 mg, 0.24 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1,2,3,4-Tetrahydroquinoline-5-sulfonamide(CAS #1155515-51-7)) (51 mg, 0.24 mmol) was added and the reactionmixture was stirred at reflux for 2 hours. The reaction mixture wasquenched with water and the organic layer was separated on a phaseseparator and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.88-7.83(m, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.21 (dd, J=7.8, 1.2 Hz, 1H), 6.99 (t,J=8.0 Hz, 1H), 6.69 (dd, J=8.1, 1.2 Hz, 1H), 3.40-3.31 (m, 1H),3.25-3.18 (m, 2H), 2.88 (t, J=6.3 Hz, 2H), 1.83-1.75 (m, 2H), 1.67-1.61(m, 2H), 1.27-1.22 (m, 2H), 1.10 (d, J=6.7 Hz, 6H). MS (ESI+) m/z 468(M+H)⁺.

Example GI-101-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (50 mg, 0.26 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (18 mg, 0.14 mmol) in anhydrous dichloromethane (1 mL), and1-[2-cyclobutyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylicacid (38 mg, 0.13 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1,2,3,4-Tetrahydroquinoline-5-sulfonamide(CAS #1155515-51-7) (27 mg, 0.13 mmol) was added and the reactionmixture was stirred at reflux for 2 hours. The reaction mixture wasquenched with water and the organic layer was separated on phaseseparator and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 Wm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.88-7.81(m, 1H), 7.57 (d, J=7.9 Hz, 1H), 7.24 (dd, J=7.8, 1.2 Hz, 1H), 7.03 (t,J=8.0 Hz, 1H), 6.73 (dd, J=8.1, 1.2 Hz, 1H), 3.89-3.76 (m, 1H),3.29-3.22 (m, 2H), 2.86 (t, J=6.4 Hz, 2H), 2.41 (dq, J=11.0, 9.1 Hz,2H), 2.14-2.04 (m, 3H), 2.04-1.92 (m, 1H), 1.84-1.77 (m, 2H), 1.65 (t,J=3.4 Hz, 2H), 1.20 (q, J=4.4 Hz, 2H). MS (ESI+) m/z 480 (M+H)⁺.

Example GI-111-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (50 mg, 0.26 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (18 mg, 0.14 mmol) in anhydrous dichloromethane (1 mL), and1-[2-cyclobutyl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylicacid (38 mg, 0.13 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Naphthalene-1-sulfonamide (CAS #606-25-7)(27 mg, 0.13 mmol) was added and the reaction mixture was stirred atreflux for 2 hours. The reaction mixture was quenched with water and theorganic layer was separated on phase separator and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound. ¹H NMR(400 MHz, methanol-d₄) δ ppm 8.57-8.47 (m, 1H), 8.38 (dd, J=7.4, 1.3 Hz,1H), 8.22 (dt, J=8.3, 1.2 Hz, 1H), 8.11-8.02 (m, 1H), 7.75 (dd, J=7.9,0.8 Hz, 1H), 7.70-7.59 (m, 3H), 7.53 (d, J=7.9 Hz, 1H), 3.56-3.43 (m,1H), 2.26-2.11 (m, 2H), 1.82-1.59 (m, 4H), 1.59-1.54 (m, 2H), 1.12 (q,J=4.4 Hz, 2H). MS (ESI+) m/z 475 (M+H)⁺.

Example GI-121-[2-cyclopropyl-5-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(2-cyclopropyl-5-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (47mg, 0.20 mmol) in anhydrous dichloromethane (2 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (58 mg, 0.30 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (22 mg, 0.18 mmol) were added and the mixture was stirred atambient temperature for 5 minutes. Quinoline-5-sulfonamide (CAS#415913-05-2) (34 mg, 0.165 mmol) was added and the reaction mixture wasstirred at ambient temperature for 2 hours. The reaction mixture wastreated with water. The aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 Mm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.05 (dt,J=8.8, 1.3 Hz, 1H), 8.96 (dd, J=4.3, 1.6 Hz, 1H), 8.41 (dd, J=7.4, 1.2Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 8.09 (s, 1H), 7.96 (d, J=2.8 Hz, 1H),7.89 (dd, J=8.5, 7.4 Hz, 1H), 7.61 (dd, J=8.8, 4.2 Hz, 1H), 7.44 (s,1H), 3.85 (d, J=6.4 Hz, 2H), 2.10 (dp, J=13.4, 6.7 Hz, 1H), 1.88 (d,J=5.3 Hz, 1H), 1.57 (d, J=3.1 Hz, 2H), 1.15 (d, J=3.1 Hz, 2H), 1.07 (d,J=6.8 Hz, 6H), 0.76 (dd, J=5.2, 2.5 Hz, 2H), 0.63 (d, J=7.1 Hz, 2H). MS(ESI+) m/z 466 (M+H)⁺.

Example GI-131-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-ethyl-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (30 mg,0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (46 mg, 0.24 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (18 mg, 0.144 mmol) in anhydrous dichloromethane (1 mL) wasadded to quinoline-5-sulfonamide (CAS #415913-05-2) (27 mg, 0.132 mmol).The reaction mixture was stirred at ambient temperature for 2 hours. Thereaction mixture was quenched with saturated aqueous NH₄Cl solution, andthe aqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 m OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.18 (ddd, J=8.7, 1.7, 0.9 Hz, 1H),8.89 (dd, J=4.3, 1.7 Hz, 1H), 8.26 (dd, J=7.3, 1.2 Hz, 1H), 8.12 (dt,J=8.5, 1.1 Hz, 1H), 7.77 (dd, J=8.5, 7.3 Hz, 1H), 7.73-7.68 (m, 1H),7.57 (dd, J=8.7, 4.3 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 4.96-4.84 (m, 1H),2.53 (q, J=7.6 Hz, 2H), 1.47 (q, J=3.9 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H),0.91 (d, J=6.2 Hz, 6H), 0.83 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 440(M+H)⁺.

Example GI-141-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-ethyl-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (30 mg,0.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (46 mg, 0.24 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (18 mg, 0.144 mmol) in anhydrous dichloromethane (1 mL) wasadded to 1,2,3,4-tetrahydroquinoline-5-sulfonamide (CAS #1155515-51-7)(CAS #415913-05-2) (28 mg, 0.132 mmol). The reaction mixture was stirredat ambient temperature for 2 hours. The reaction mixture was quenchedwith saturated aqueous NH₄Cl solution, and the aqueous layer wasextracted with dichloromethane. The organic layers were combined, driedover MgSO₄, filtered and concentrated. The crude material was purifiedby reverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm,flow rate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1%diethylamine to give the title compound. ¹H NMR (400 MHz, methanol-d₄) δppm 7.73 (d, J=2.4 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.24 (dd, J=7.7, 1.2Hz, 1H), 6.89 (t, J=7.9 Hz, 1H), 6.57 (dd, J=8.0, 1.2 Hz, 1H), 5.13(hept, J=6.1 Hz, 1H), 3.26-3.19 (m, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.55(q, J=7.6 Hz, 2H), 1.85 (dt, J=11.0, 6.4 Hz, 2H), 1.50 (q, J=3.9 Hz,2H), 1.27-1.24 (m, 6H), 1.21 (t, J=7.6 Hz, 3H), 0.85 (q, J=3.9 Hz, 2H).MS (ESI+) m/z 444 (M+H)⁺.

Example GI-151-[2-(pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (38 mg, 0.20 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (14 mg, 0.11 mmol) in anhydrous dichloromethane (1 mL), and1-[2-pyrrolidin-1-yl-6-(trifluoromethyl)-3-pyridyl]cyclopropanecarboxylicacid (30 mg, 0.10 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(21 mg, 0.10 mmol) was added and the reaction mixture was stirred atreflux for 1 hour. The reaction mixture was quenched with water and theorganic layer was separated on a phase separator and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.18 ddd, J=8.7, 1.7, 0.8 Hz, 1H),8.88 (dd, J=4.3, 1.7 Hz, 1H), 8.28 (dd, J=7.3, 1.2 Hz, 1H), 8.12 (dt,J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3 Hz, 1H), 7.57 (dd, J=8.7, 4.3Hz, 1H), 7.50 (dd, J=7.6, 0.9 Hz, 1H), 6.84 (d, J=7.5 Hz, 1H), 3.33-3.16(m, 4H), 1.55 (d, J=4.3 Hz, 2H, 1.46-1.30 (m, 4H), 0.97 (d, J=4.5 Hz,2H). MS (ESI+) m/z 491 (M+H)⁺.

Example GI-161-{2-methoxy-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(5-isopropoxy-2-methoxy-4-pyridyl)cyclopropanecarboxylic acid (29 mg,0.115 mmol) in anhydrous dichloromethane (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (44 mg, 0.23 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (17 mg, 0.138 mmol) were added and the mixture was stirredat ambient temperature for 5 minutes. Quinoline-5-sulfonamide (CAS#415913-05-2) (26 mg, 0.126 mmol) was added and the reaction mixture wasstirred at ambient temperature for 2.5 hours. The reaction mixture wastreated with water and aqueous layer was extracted with dichloromethane.The organic layers were combined, dried over MgSO4, filtered andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.16 (ddd, J=8.8, 1.7, 0.9Hz, 1H), 8.88 (dd, J=4.3, 1.7 Hz, 1H), 8.26 (dd, J=7.3, 1.3 Hz, 1H),8.12 (dt, J=8.5, 1.1 Hz, 1H), 7.77 (dd, J=8.5, 7.3 Hz, 1H), 7.57 (dd,J=8.7, 4.3 Hz, 1H), 7.50 (s, 1H), 6.61 (s, 1H), 4.17 (hept, J=6.0 Hz,1H), 3.82 (s, 3H), 1.43 (q, J=3.9 Hz, 2H), 0.90-0.82 (m, 8H). MS (ESI+)m/z 442 (M+H)⁺.

Example GI-171-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(4-isopropoxy-6-methoxy-3-pyridyl)cyclopropanecarboxylic acid (40 mg,0.159 mmol) in anhydrous dichloromethane (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (61 mg, 0.318 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (23 mg, 0.191 mmol) were added and the mixture was stirredat ambient temperature for 5 minutes. Quinoline-5-sulfonamide (CAS#415913-05-2) (36 mg, 0.175 mmol) was added and the reaction mixture wasstirred at ambient temperature for 2.5 hours. The reaction mixture wastreated with water. The aqueous layer was extracted withdichloromethane, and the organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.19(ddd, J=8.8, 1.7, 0.9 Hz, 1H), 8.88 (dd, J=4.3, 1.7 Hz, 1H), 8.24 (dd,J=7.3, 1.2 Hz, 1H), 8.11 (dt, J=8.5, 1.1 Hz, 1H), 7.77 (dd, J=8.5, 7.3Hz, 1H), 7.69 (s, 1H), 7.58 (dd, J=8.8, 4.3 Hz, 1H), 6.11 (s, 1H), 4.34(hept, J=6.0 Hz, 1H), 3.83 (s, 3H), 1.44 (q, J=3.8 Hz, 2H), 0.90 (d,J=6.0 Hz, 6H), 0.80 (q, J=3.8 Hz, 2H). MS (ESI+) m/z 442 (M+H)⁺.

Example GI-181-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(4-isopropoxy-6-methoxy-3-pyridyl)cyclopropanecarboxylic acid (25 mg,0.10 mmol) in anhydrous dichloromethane (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (38 mg, 0.20 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (15 mg, 0.12 mmol) were added and the mixture was stirred atambient temperature for 5 minutes. 2-Methylquinoline-5-sulfonamide (24mg, 0.11 mmol) was added and the reaction mixture was stirred at ambienttemperature for 2.5 hours. The reaction mixture was treated with water.The aqueous layer was extracted with dichloromethane, and the organiclayers were combined, dried over MgSO₄, filtered and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.04 (dd, J=8.9, 0.8 Hz, 1H), 8.17(dd, J=7.3, 1.2 Hz, 1H), 8.02 (dt, J=8.5, 1.1 Hz, 1H), 7.71 (dd, J=8.5,7.3 Hz, 1H), 7.68 (s, 1H), 7.46 (d, J=8.9 Hz, 1H), 6.10 (s, 1H), 4.34(hept, J=6.0 Hz, 1H), 3.83 (s, 3H), 2.73 (s, 3H), 1.43 (q, J=3.8 Hz,2H), 0.91 (d, J=6.0 Hz, 6H), 0.79 (q, J=3.8 Hz, 2H). MS (ESI+) m/z 456(M+H)⁺.

Example GI-191-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(5-isobutoxy-2-methoxy-4-pyridyl)cyclopropanecarboxylic acid (40 mg,0.15 mmol) in anhydrous dichloromethane (3 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (61 mg, 0.30 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (19 mg, 0.15 mmol) were added, followed byquinoline-5-sulfonamide (CAS #415913-05-2) (28 mg, 0.135 mmol). Thereaction mixture was stirred at ambient temperature for 1 hour. Thereaction mixture was quenched with saturated aqueous NaHCO₃ solution,and the organic layer was separated on phase separator and concentrated.The crude material was purified by reverse-phase HPLC Waters XBridge™C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the compound withNN-dimethylaminopyridine. The residue was washed with saturated aqueousNH₄Cl solution and extracted with ethyl_(a)cetate. The organic layer wasseparated, dried over Na₂SO₄, filtered and concentrated to give thetitle compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.99 (dd, J=4.2,1.6 Hz, 1H), 8.86 (ddd, J=8.7, 1.6, 0.9 Hz, 1H), 8.42 (dd, J=7.4, 1.2Hz, 1H), 8.32 (dt, J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.4 Hz, 1H),7.65 (s, 1H), 7.49 (dd, J=8.8, 4.2 Hz, 1H), 6.58 (s, 1H), 3.89 (s, 3H),3.44 (d, J=6.4 Hz, 2H), 1.59-1.44 (m, 3H), 0.97 (q, J=4.2 Hz, 2H), 0.74(d, J=6.7 Hz, 6H). MS (ESI+) m/z 456 (M+H)⁺.

Example GI-201-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(5-isobutoxy-2-methoxy-4-pyridyl)cyclopropanecarboxylic acid (40 mg,0.15 mmol) in anhydrous dichloromethane (3 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (61 mg, 0.30 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (19 mg, 0.15 mmol) were added, followed by2-methylquinoline-5-sulfonamide (30 mg, 0.135 mmol). The reactionmixture was stirred at ambient temperature for 2 hours. The reactionmixture was quenched with saturated aqueous NaHCO₃ solution, and theorganic layer was separated on phase separator and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the compound withN,N-Ddimethylaminopyridine. The residue was washed with saturatedaqueous NH₄Cl solution and extracted with ethyl acetate. The organiclayer was separated, dried over Na₂SO₄, filtered and concentrated togive the title compound. MS (ESI+) m/z 470 (M+H)⁺.

Example GI-21N-(1H-indole-4-sulfonyl)-1-[2-methoxy-5-(2-methylpropoxy)pyridin-4-yl]cyclopropane-1-carboxamide

Into a vial, to a solution of1-(5-isobutoxy-2-methoxy-4-pyridyl)cyclopropanecarboxylic acid (201 mg,0.76 mmol) in anhydrous dichloromethane (7.6 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (291 mg, 1.52 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (93 mg, 0.76 mmol) were added, followed by1H-indole-4-sulfonamide (149 mg, 0.76 mmol). The reaction mixture wasstirred at ambient temperature for 2 hours and heated at 55° C. for 1.5hours. The solvent was removed and the residue was acidified withNaH₂PO₄ 0.2M aqueous solution (5 mL) to protonate4-dimethylaminopyridine (CAS #1122-58-3). The mixture was partitionedbetween water and ethyl acetate and the aqueous layer was extracted withethyl acetate. The organic layer was washed with water, dried overMgSO₄, filtered and concentrated. The crude material was washed withaqueous HCl (1N, 1 mL), and triturated in water. Diethyl ether and theprecipitate was filtered to give the title compound. ¹H NMR (400 MHz,methanol-d₄) δ ppm 11.98 (s, 1H), 8.47-8.39 (m, 2H), 8.33 (s, 1H), 8.19(t, J=2.8 Hz, 1H), 7.96 (t, J=7.9 Hz, 1H), 7.48 (t, J=2.5 Hz, 1H), 7.40(s, 1H), 4.57 (s, 3H), 4.10 (d, J=6.5 Hz, 2H), 2.10 (q, J=4.4 Hz, 2H),2.07-1.97 (m, 1H), 1.75 (q, J=4.5 Hz, 2H), 1.44 (d, J=6.7 Hz, 6H). MS(ESI+) m/z 444 (M+H)⁺.

Example GI-221-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(5-cyclobutyl-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (65mg, 0.236 mmol) in anhydrous dimethyl sulfoxide (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (90 mg, 0.472 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (29 mg, 0.191 mmol) were added and the mixture was stirredat ambient temperature for 5 minutes. Quinoline-5-sulfonamide (CAS#415913-05-2) (54 mg, 0.26 mmol) was added and the reaction mixture wasstirred at ambient temperature overnight. The mixture was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.14(ddd, J=8.7, 1.7, 0.8 Hz, 1H), 8.85 (dd, J=4.3, 1.7 Hz, 1H), 8.22 (dd,J=7.3, 1.2 Hz, 1H), 8.09 (dt, J=8.5, 1.1 Hz, 1H), 7.74 (dd, J=8.5, 7.3Hz, 1H), 7.68 (dd, J=2.4, 0.7 Hz, 1H), 7.53 (dd, J=8.7, 4.3 Hz, 1H),7.34 (d, J=2.4 Hz, 1H), 4.92-4.80 (m, 1H), 3.48-3.35 (m, 1H), 2.31-2.19(m, 2H), 2.16-1.93 (m, 3H), 1.88-1.79 (m, 1H), 1.43 (q, J=3.9 Hz, 2H),0.88 (d, J=6.1 Hz, 6H), 0.80 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 466(M+H)⁺.

Example GI-231-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinone-5-sine-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(5-cyclobutyl-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (65mg, 0.236 mmol) in anhydrous dimethyl sulfoxide (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (90 mg, 0.472 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (29 mg, 0.191 mmol) were added and the mixture was stirredat ambient temperature for 5 minutes. 2-Methylquinoline-5-sulfonamide(58 mg, 0.26 mmol) was added and the reaction mixture was stirred atambient temperature overnight. The mixture was purified by reverse-phaseHPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to givethe title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.02 (d, J=8.6Hz, 1H), 8.18 (dd, J=7.3, 1.2 Hz, 1H), 8.03 (dt, J=8.5, 1.1 Hz, 1H),7.79-7.64 (m, 2H), 7.44 (d, J=8.9 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H),4.95-4.81 (m, 1H), 3.45 (p, J=8.6 Hz, 1H), 2.74 (s, 3H), 2.32-2.23 (m,2H), 2.18-1.98 (m, 3H), 1.90-1.80 (m, 2H), 1.46 (q, J=3.9 Hz, 2H), 0.90(d, J=6.1 Hz, 6H), 0.82 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 481 (M+H)⁺.

Example GI-241-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(5-cyclobutyl-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (65mg, 0.236 mmol) in anhydrous dimethyl sulfoxide (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (90 mg, 0.472 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (29 mg, 0.191 mmol) were added and the mixture was stirredat ambient temperature for 5 minutes. 1H-Indole-4-sulfonamide (51 mg,0.26 mmol) was added and the reaction mixture was stirred at ambienttemperature overnight. The mixture was purified by reverse-phase HPLCWaters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.74 (dd, J=2.4, 0.8 Hz,1H), 7.62 (dd, J=7.5, 0.9 Hz, 1H), 7.52 (dt, J=8.1, 0.9 Hz, 1H), 7.43(d, J=2.4 Hz, 1H), 7.32 (d, J=3.2 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 6.88(dd, J=3.1, 0.9 Hz, 1H), 5.07 (hept, J=6.1 Hz, 1H), 3.47 (p, J=8.5 Hz,1H), 2.35-2.27 (m, 3H), 2.21-1.98 (m, 3H), 1.94-1.83 (m, 1H), 1.50 (q,J=3.9 Hz, 2H), 1.14 (d, J=6.1 Hz, 6H), 0.86 (q, J=3.9 Hz, 2H). MS (ESI+)m/z 454 (M+H)⁺.

Example GI-251-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (50 mg, 0.262 mmol), 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.262 mmol) and 2-methylquinoline-5-sulfonamide (50mg, 0.24 mmol) were charged. A solution of1-(2-cyclobutyl-5-isopropoxypyridin-4-yl)cyclopropanecarboxylic acid (60mg, 0.218 mmol) in anhydrous dichloromethane (1 mL) was added and themixture was stirred at reflux overnight. Quinoline-5-sulfonamide (CAS#41591-05-2) (50 mg, 0.24 mmol) was added and the reaction mixture wasstirred at ambient temperature overnight. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution. The aqueous layer wasextracted with dichloromethane. The organic layers were combined, driedover MgSO₄, filtered and concentrated. The crude material was purifiedby reverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm,flow rate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1%diethylamine to give the title compound. ¹H NMR (400 MHz, methanol-d₄) δppm 9.16 (ddd, J=8.7, 1.7, 0.8 Hz, 1H), 8.89 (dd, J=4.3, 1.7 Hz, 1H),8.26 (dd, J=7.3, 1.2 Hz, 1H), 8.12 (dt, J=8.4, 1.1 Hz, 1H), 7.88 (s,1H), 7.77 (dd, J=8.5, 7.3 Hz, 1H), 7.57 (dd, J=8.7, 4.3 Hz, 1H), 7.09(s, 1H), 4.34 (hept, J=6.0 Hz, 1H), 3.65-3.51 (m, 1H), 2.36-2.16 (m,4H), 2.12-1.96 (m, 1H), 1.93-1.80 (m, 1H), 1.48 (q, J=3.9 Hz, 2H), 0.94(d, J=6.0 Hz, 6H), 0.88 (q, J=4.0 Hz, 2H). MS (ESI+) m/z 466 (M+H)⁺.

Example GI-261-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (50 mg, 0.262 mmol), 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.262 mmol) and 2-methylquinoline-5-sulfonamide (53mg, 0.24 mmol) were charged. A solution of1-(2-cyclobutyl-5-isopropoxypyridin-4-yl)cyclopropanecarboxylic acid (60mg, 0.218 mmol) in anhydrous dichloromethane (1 mL) was added and themixture was stirred at reflux overnight. Naphthalene-1-sulfonamide (CAS#606-25-7) (50 mg, 0.24 mmol) was added and the reaction mixture wasstirred at ambient temperature overnight. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution. The aqueous layer wasextracted with dichloromethane. The organic layers were combined, driedover MgSO₄, filtered and concentrated. The crude material was purifiedby reverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm,flow rate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1%diethylamine to give the title compound. ¹H NMR (400 MHz, methanol-d₄) δppm 9.02 (dd, J=8.8, 0.8 Hz, 1H), 8.18 (dd, J=7.3, 1.2 Hz, 1H), 8.04(dt, J=8.5, 1.1 Hz, 1H), 7.88 (s, 1H), 7.72 (dd, J=8.5, 7.3 Hz, 1H),7.45 (d, J=8.8 Hz, 1H), 7.09 (s, 1H), 4.34 (hept, J=6.0 Hz, 1H), 3.58(dddd, J=17.6, 9.3, 8.2, 1.0 Hz, 1H), 2.75 (s, 3H), 2.37-2.16 (m, 4H),2.13-1.97 (m, 1H), 1.93-1.81 (m, 1H), 1.48 (q, J=3.9 Hz, 2H), 0.94 (d,J=6.0 Hz, 6H), 0.87 (q, J=4.0 Hz, 2H). MS (ESI+) m/z 480 (M+H)⁺.

Example GI-271-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (50 mg, 0.262 mmol), 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.262 mmol) and 1H-indole-4-sulfonamide (47 mg, 0.24mmol) were charged. A solution of1-(2-cyclobutyl-5-isopropoxypyridin-4-yl)cyclopropanecarboxylic acid (60mg, 0.218 mmol) in anhydrous dichloromethane (1 mL) was added and themixture was stirred at reflux overnight. Naphthalene-1-sulfonamide (CAS#606-25-7) (CAS #41591-05-2) (50 mg, 0.24 mmol) was added and thereaction mixture was stirred at ambient temperature overnight. Thereaction mixture was quenched with saturated aqueous NH₄Cl solution. Theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 m OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 8.15 (s, 1H), 8.05 (s, 1H), 7.76(dd, J=7.6, 0.9 Hz, 1H), 7.70 (dt, J=8.2, 1.0 Hz, 1H), 7.44 (d, J=3.2Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.17 (s, 1H), 6.81 (dd, J=3.2, 0.9 Hz,1H), 4.54 (hept, J=6.0 Hz, 1H), 3.63 (dddd, J=17.6, 9.3, 8.2, 1.0 Hz,1H), 2.39-2.20 (m, 4H), 2.14-1.98 (m, 1H), 1.95-1.82 (m, 1H), 1.47-1.35(m, 2H), 1.09 (d, J=6.0 Hz, 6H), 1.08-1.04 (m, 2H). MS (ESI+) m/z 454(M+H)⁺.

Example GI-281-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

In a microwave vial, to a solution of1-(5-cyclobutyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(50 mg, 0.174 mmol) in anhydrous NN-dimethylformamide (1 mL) under N₂,quinoline-5-sulfonamide (CAS #415913-05-2) (40 mg, 0.191 mmol) andNN-diisopropylethylamine (62 μL, 0.348 mmol) were added and the mixturewas stirred at ambient temperature for 5 minutes. Propylphosphonicanhydride solution ˜50% in N,N-dimethylformamide (CAS #68957-94-8) (179μL, 0.209 mmol) was added and the reaction mixture was heated at 60° C.for 2 hours. The reaction mixture was cooled down at ambient temperatureand the solvent was removed. The mixture was quenched with saturatedaqueous NaHCO₃ solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.21(ddd, J=8.8, 1.6, 0.8 Hz, 1H), 8.90 (dd, J=4.3, 1.7 Hz, 1H), 8.28 (dd,J=7.3, 1.2 Hz, 1H), 8.13 (dt, J=8.4, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3Hz, 1H), 7.63-7.55 (m, 2H), 7.42 (d, J=2.4 Hz, 1H), 3.44-3.31 (m, 1H),3.21 (d, J=6.3 Hz, 4H), 2.25 (dddd, J=8.6, 6.8, 4.9, 3.5 Hz, 2H),2.12-1.91 (m, 3H), 1.90-1.77 (m, 1H), 1.57 (q, J=3.6 Hz, 2H), 1.49-1.38(m, 4H), 0.98 (q, J=3.5 Hz, 2H). MS (ESI+) m/z 477 (M+H)⁺.

Example GI-291-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(5-cyclobutyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(60 mg, 0.209 mmol) in anhydrous dichloromethane (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (48 mg, 0.251 mmol), 4-dimethylaminopyridine (CAS#1122-58-3) (31 mg, 0.251 mmol) and 2-methylquinoline-5-sulfonamide (51mg, 0.23 mmol) were added and the mixture was stirred at refluxovernight. 2-Methylquinoline-5-sulfonamide (23 mg, 0.104 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (20 mg, 0.104 mmol) and anhydrous tetrahydrofuran (1 mL)were added and the reaction mixture was stirred and heated at 65° C.overnight. The reaction mixture was cooled down at ambient temperatureand concentrated. The residue was quenched with saturated aqueous NH₄Clsolution and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.10 (dd, J=8.9, 0.9 Hz,1H), 8.23 (dd, J=7.3, 1.2 Hz, 1H), 8.05 (dt, J=8.5, 1.1 Hz, 1H), 7.74(dd, J=8.5, 7.3 Hz, 1H), 7.65 (dd, J=2.4, 0.7 Hz, 1H), 7.47 (d, J=8.9Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 3.47-3.34 (m, 1H), 3.20 (d, J=6.3 Hz,4H), 2.75 (s, 3H), 2.34-2.22 (m, 2H), 2.15-1.94 (m, 3H), 1.92-1.80 (m,1H), 1.57 (q, J=3.6 Hz, 2H), 1.51-1.41 (m, 4H), 0.96 (q, J=3.5 Hz, 2H).MS (ESI+) m/z 491 (M+H)⁺.

Example GI-301-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

In a microwave vial, to a solution of1-(5-cyclobutyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(55 mg, 0.192 mmol) in anhydrous NN-dimethylformamide (1 mL) under N₂,1H-indole-4-sulfonamide (41 mg, 0.211 mmol) and NN-diisopropylethylamine(67 μL, 0.384 mmol) were added, The mixture was stirred at ambienttemperature for 5 minutes. Propylphosphonic anhydride solution ˜50% inN,N-dimethylformamide (CAS #68957-94-8) (198 μL, 0.23 mmol) was addedand the reaction mixture was heated at 60° C. for 2 hours. The reactionmixture was cooled down at ambient temperature and the solvent wasremoved. The mixture was quenched with saturated aqueous NaHCO₃solution, and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 m OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.63 (dd, J=2.4, 0.7 Hz,1H), 7.60 (dd, J=7.5, 0.9 Hz, 1H), 7.49 (dt, J=8.1, 1.0 Hz, 1H), 7.42(d, J=2.4 Hz, 1H), 7.31 (d, J=3.2 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.88(dd, J=3.1, 0.9 Hz, 1H), 3.44-3.34 (m, 1H), 3.33-3.27 (m, 4H), 2.31-2.19(m, 2H), 2.15-1.94 (m, 3H), 1.89-1.77 (m, 1H), 1.62 (q, J=3.6 Hz, 2H),1.58-1.48 (m, 4H), 0.96 (q, J=3.5 Hz, 2H). MS (ESI+) m/z 465 (M+H)⁺.

Example GI-311-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide

In a microwave vial, to a solution of1-(5-cyclobutyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(55 mg, 0.192 mmol) in anhydrous N,N-dimethylformamide (1 mL) under N₂,1,2,3,4-tetrahydroquinoline-5-sulfonamide (CAS #1155515-51-7) (45 mg,0.211 mmol) and N,N-diisopropylethylamine (67 μL, 0.384 mmol) wereadded. The mixture was stirred at ambient temperature for 5 minutes.Propylphosphonic anhydride solution ˜50% in N,N-dimethylformamide (CAS#68957-94-8) (198 μL, 0.23 mmol) was added and the reaction mixture washeated at 60° C. for 2 hours. The reaction mixture was cooled down atambient temperature and the solvent was removed. The mixture wasquenched with saturated aqueous NaHCO₃ solution, and the aqueous layerwas extracted with dichloromethane. The organic layers were combined,dried over MgSO₄, filtered and concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 Mm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.84 (s, 1H), 7.41 (s, 1H), 7.03 (dd,J=7.8, 1.3 Hz, 1H), 6.96 (t, J=7.9 Hz, 1H), 6.65 (d, J=8.0 Hz, 1H),3.54-3.26 (m, 4H), 3.17 (dd, J=6.5, 4.6 Hz, 2H), 2.92 (t, J=6.4 Hz, 2H),2.29-2.18 (m, 2H), 2.16-1.86 (m, 4H), 1.86-1.70 (m, 6H), 1.55 (d, J=3.2Hz, 2H), 1.16 (q, J=4.0 Hz, 2H). MS (ESI+) m/z 481 (M+H)⁺.

Example GI-321-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(5-cyclopropyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(72 mg, 0.264 mmol) in anhydrous dichloromethane (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (60 mg, 0.317 mmol), 4-dimethylaminopyridine (CAS#1122-58-3) (39 mg, 0.317 mmol) and quinoline-5-sulfonamide (CAS#415913-05-2) (64 mg, 0.29 mmol) were added and the mixture was stirredat reflux overnight. Quinoline-5-sulfonamide (CAS #415913-05-2) (27 mg,0.132 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (25 mg, 0.132 mmol) and anhydrous tetrahydrofuran (1mL) were added and the reaction mixture was stirred and heated at 65° C.overnight. The reaction mixture was cooled down at ambient temperatureand the solvent was concentrated. The residue was quenched withsaturated aqueous NH₄Cl solution and the aqueous layer was extractedwith dichloromethane. The organic layers were combined, dried overMgSO₄, filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.22(ddd, J=8.7, 1.7, 0.9 Hz, 1H), 8.89 (dd, J=4.3, 1.7 Hz, 1H), 8.29 (dd,J=7.3, 1.3 Hz, 1H), 8.11 (dt, J=8.5, 1.1 Hz, 1H), 7.77 (dd, J=8.5, 7.3Hz, 1H), 7.64-7.55 (m, 2H), 7.15 (d, J=2.4 Hz, 1H), 3.17 (d, J=6.3 Hz,4H), 1.73 (tt, J=8.4, 5.1 Hz, 1H), 1.54 (q, J=3.6 Hz, 2H), 1.48-1.38 (m,4H), 0.93 (q, J=3.5 Hz, 2H), 0.89-0.78 (m, 2H), 0.57-0.48 (m, 2H). MS(ESI+) m/z 463 (M+H)⁺.

Example GI-331-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(5-cyclopropyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(72 mg, 0.264 mmol) in anhydrous dichloromethane (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (61 mg, 0.317 mmol), 4-dimethylaminopyridine (CAS#1122-58-3) (39 mg, 0.317 mmol) and 2-methylquinoline-5-sulfonamide (64mg, 0.29 mmol) were added and the mixture was stirred at refluxovernight. 2-Methylquinoline-5-sulfonamide (29 mg, 0.132 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (25 mg, 0.132 mmol) and anhydrous tetrahydrofuran (1 mL)were added and the reaction mixture was stirred and heated at 65° C.overnight. The reaction mixture was cooled down at ambient temperatureand solvent was concentrated. The residue was quenched with saturatedaqueous NH₄Cl solution and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.07(dd, J=8.9, 0.9 Hz, 1H), 8.20 (dd, J=7.3, 1.2 Hz, 1H), 8.07-7.99 (m,1H), 7.72 (dd, J=8.5, 7.3 Hz, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.47 (d,J=8.9 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 3.16 (d, J=6.2 Hz, 4H), 2.74 (s,3H), 1.74 (tt, J=8.5, 5.1 Hz, 1H), 1.53 (q, J=3.6 Hz, 2H), 1.47-1.39 (m,4H), 0.92 (q, J=3.5 Hz, 2H), 0.89-0.79 (m, 2H), 0.58-0.50 (m, 2H). MS(ESI+) m/z 477 (M+H)⁺.

Example GI-341-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(5-cyclopropyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(72 mg, 0.264 mmol) in anhydrous dichloromethane (1 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (61 mg, 0.317 mmol), 4-dimethylaminopyridine (CAS#1122-58-3) (39 mg, 0.317 mmol) and 1H-indole-4-sulfonamide (57 mg, 0.29mmol) were added and the mixture was stirred at reflux overnight.1H-Indole-4-sulfonamide (26 mg, 0.132 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (25 mg, 0.132 mmol) and anhydrous tetrahydrofuran (1 mL)were added and the reaction mixture was stirred and heated at 65° C.overnight. The reaction mixture was cooled down at ambient temperatureand solvent was concentrated. The residue was quenched with saturatedaqueous NH₄Cl solution and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.62(dd, J=7.4, 0.9 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 7.48 (dt, J=8.1, 1.0Hz, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 7.10 (t, J=7.8Hz, 1H), 6.85 (dd, J=3.1, 0.9 Hz, 1H), 3.27 (d, J=6.3 Hz, 4H), 1.73 (tt,J=8.4, 5.1 Hz, 1H), 1.58 (q, J=3.7 Hz, 2H), 1.56-1.49 (m, 4H), 0.93 (q,J=3.6 Hz, 2H), 0.88-0.80 (m, 2H), 0.60-0.49 (m, 2H). MS (ESI+) m/z 451(M+H)⁺.

Example GI-351-[5-chloro-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

In a microwave vial, to a mixture with1-(5-ethyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid and1-(5-chloro-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid (70mg, 0.27 mmol) in anhydrous N,N-dimethylformamide (1 mL) under N₂,quinoline-5-sulfonamide (CAS #415913-05-2) (62 mg, 0.297 mmol) andNN-diisopropylethylamine (94 μL, 0.54 mmol) were added and the mixturewas stirred at ambient temperature for 5 minutes. Propylphosphonicanhydride solution ˜50% in N,N-dimethylformamide (CAS #68957-94-8) (306μL, 0.356 mmol) was added and the reaction mixture was heated at 60° C.for 2 hours. The reaction mixture was cooled down at ambient temperatureand the solvent was removed. The mixture was quenched with saturatedaqueous NaHCO₃ solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.12(dt, J=8.7, 1.3 Hz, 1H), 8.97 (dd, J=4.3, 1.6 Hz, 1H), 8.42 (dd, J=7.4,1.2 Hz, 1H), 8.28 (dt, J=8.5, 1.1 Hz, 1H), 7.89-7.86 (m, 1H), 7.66 (dd,J=8.8, 4.3 Hz, 1H), 7.58 (d, J=2.5 Hz, 1H), 7.56 (d, J=2.5 Hz, 1H),3.28-3.20 (m, 4H), 1.97-1.89 (m, 4H), 1.69 (q, J=4.1 Hz, 2H), 1.18 (q,J=4.1 Hz, 2H). MS (ESI−) m/z 455 & 457 (M−H)⁻.

Example GI-361-[5-chloro-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

In a microwave vial, to a mixture of1-(5-ethyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid and1-(5-chloro-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid (70mg, 0.27 mmol) in anhydrous N,N-dimethylformamide (1 mL) under N₂,2-methylquinoline-5-sulfonamide (66 mg, 0.297 mmol) andN,N-diisopropylethylamine (94 μL, 0.54 mmol) were added. The mixture wasstirred at ambient temperature for 5 minutes. Propylphosphonic anhydridesolution ˜50% in N,N-dimethylformamide (CAS #68957-94-8) (306 μL, 0.356mmol) was added and the reaction mixture was heated at 60° C. for 2hours. The reaction mixture was cooled down at ambient temperature andthe solvent was removed. The mixture was quenched with saturated aqueousNaHCO₃ solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.01 (d,J=8.9 Hz, 1H), 8.33 (dd, J=7.4, 1.2 Hz, 1H), 8.20-8.14 (m, 1H), 8.07 (s,1H), 7.87 (d, J=2.5 Hz, 1H), 7.84 (dd, J=8.5, 7.4 Hz, 1H), 7.56-7.54 (m,1H), 3.27-3.18 (m, 4H), 1.96-1.87 (m, 2H), 1.52 (dq, J=6.7, 4.2, 3.1 Hz,4H), 1.16 (q, J=4.0 Hz, 2H). MS (ESI−) m/z 469 & 471 (M−H)⁻.

Example GI-371-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

In a microwave vial, to a solution of1-(5-ethyl-2-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid (68mg, 0.26 mmol) in anhydrous NN-dimethylformamide (1.5 mL) under N₂,1H-indole-4-sulfonamide (56 mg, 0.286 mmol) and NN-diisopropylethylamine(91 μL, 0.52 mmol) were added and the mixture was stirred at ambienttemperature for 5 minutes. Propylphosphonic anhydride solution ˜50% inN,N-dimethylformamide (CAS #68957-94-8) (267 μL, 0.312 mmol) was addedand the reaction mixture was heated at 60° C. for 1.5 hours. Thereaction mixture was cooled down at ambient temperature and the solventwas removed. The mixture was quenched with saturated aqueous NaHCO₃solution, and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.64-7.60 (m, 1H), 7.58(d, J=2.4 Hz, 1H), 7.49 (dt, J=8.2, 0.9 Hz, 1H), 7.41 (dd, J=5.4, 2.7Hz, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.88-6.81 (m,1H), 3.29-3.25 (m, 4H), 2.47 (q, J=7.6 Hz, 2H), 1.60 (q, J=3.6 Hz, 2H),1.56-1.51 (m, 4H), 1.16 (t, J=7.6 Hz, 3H), 0.97 (q, J=3.6 Hz, 2H). MS(ESI+) m/z 439 (M+H)⁺.

Example GI-381-{6-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (77 mg, 0.40 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (27 mg, 0.22 mmol) in anhydrous dichloromethane (2 mL),1-(6-cyclobutyl-3-isopropoxy-2-pyridyl)cyclopropanecarboxylic acid (55mg, 0.20 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1H-Indole-4-sulfonamide (39 mg, 0.20 mmol)was added and the reaction mixture was stirred at reflux for 1 hour. Thereaction mixture was treated with water and organic layer was separatedon a phase separator and concentrated. The crude material was purifiedby reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm,flow rate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1%diethylamine to give the title compound. ¹H NMR (400 MHz, methanol-d₄) δppm 7.60 (dd, J=7.4, 0.9 Hz, 1H), 7.47 (dt, J=8.1, 0.9 Hz, 1H), 7.28 (d,J=3.1 Hz, 1H), 7.15 (d, J=8.5 Hz, 1H), 7.08 (dt, J=7.8, 3.6 Hz, 2H),6.89 (dd, J=3.1, 0.9 Hz, 1H), 4.44 (hept, J=6.0 Hz, 1H), 3.62-3.49 (m,1H), 2.33-2.12 (m, 4H), 2.06-1.90 (m, 1H), 1.89-1.77 (m, 1H), 1.53 (q,J=3.9 Hz, 2H, 1.03 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 454 (M+H)⁺.

Example GI-391-{6-cyclobutyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (77 mg, 0.40 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (27 mg, 0.22 mmol) in anhydrous dichloromethane (2 mL),1-(6-cyclobutyl-3-isopropoxy-2-pyridyl)cyclopropanecarboxylic acid (55mg, 0.20 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(41 mg, 0.20 mmol) was added and the reaction mixture was stirred atreflux for 1 hour. The reaction mixture was treated with water andorganic layer was separated on a phase separator and was concentrated.The crude material was purified by reverse-phase HPLC Waters XBridge™C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.23 (ddd, J=8.7, 1.7, 0.8 Hz, 1H),8.90 (dd, J=4.3, 1.7 Hz, 1H), 8.27 (dd, J=7.3, 1.2 Hz, 1H), 8.13 (dt,J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3 Hz, 1H), 7.59 (dd, J=8.7, 4.3Hz, 1H), 7.10 (q, J=8.4 Hz, 2H), 4.31 (hept, J=6.0 Hz, 1H), 3.62-3.49(m, 1H), 2.32-2.12 (m, 4H), 2.08-1.92 (m, 1H), 1.90-1.76 (m, 1H), 1.52(q, J=3.8 Hz, 2H), 1.05 (q, J=3.9 Hz, 2H), 0.93 (d, J=6.0 Hz, 6H). MS(ESI+) m/z 466 (M+H)⁺.

Example GI-401-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-ethyl-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (69 mg,0.277 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (64 mg, 0.332 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (40 mg, 0.332 mmol) in anhydrous dichloromethane (2 mL) wasadded to 2-methylquinoline-5-sulfonamide (51 mg, 0.228 mmol). Thereaction mixture was stirred at reflux for 24 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.02 (dd, J=8.9, 0.8 Hz, 1H), 8.15(dd, J=7.3, 1.2 Hz, 1H), 8.03 (dt, J=8.5, 1.1 Hz, 1H), 7.75-7.66 (m,2H), 7.44 (d, J=8.9 Hz, 1H), 7.32 (d, J=2.4 Hz, 1H), 4.96-4.84 (m, 1H),2.73 (s, 3H), 2.52 (q, J=7.6 Hz, 2H), 1.46 (q, J=3.8 Hz, 2H), 0.90 (d,J=6.1 Hz, 6H), 0.82 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 454 (M+H)⁺.

Example GI-411-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-ethyl-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (69 mg,0.277 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (64 mg, 0.332 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (40 mg, 0.332 mmol) in anhydrous dichloromethane (2 mL) wasadded to 1H-indole-4-sulfonamide (54 mg, 0.277 mmol). The reactionmixture was stirred at reflux for 24 hours. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution, and the aqueous layerwas extracted with dichloromethane. The organic layers were combined,dried over MgSO₄, filtered and concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.76-7.70 (m, 1H), 7.58 (dd, J=7.4,0.9 Hz, 1H), 7.48 (dt, J=8.2, 0.9 Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.29(d, J=3.1 Hz, 1H), 7.09 (dd, J=8.1, 7.4 Hz, 1H), 6.89 (dd, J=3.1, 0.9Hz, 1H), 5.09 (hept, J=6.1 Hz, 1H), 2.52 (q, J=7.6 Hz, 2H), 1.53 (q,J=3.8 Hz, 2H), 1.23-1.14 (m, 9H), 0.86 (q, J=3.9 Hz, 2H). MS (ESI+) m/z428 (M+H)⁺.

Example GI-421-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isobutoxy-5-methyl-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (55 mg, 0.288 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (35 mg, 0.288 mmol) in anhydrous dichloromethane (2 mL) wasadded to quinoline-5-sulfonamide (CAS #415913-05-2) (50 mg, 0.24 mmol).The reaction mixture was stirred at reflux for 24 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.10 (ddd, J=8.8, 1.7, 0.9 Hz, 1H),8.90 (dd, J=4.3, 1.7 Hz, 1H), 8.26 (dd, J=7.3, 1.2 Hz, 1H), 8.13 (dt,J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3 Hz, 1H), 7.70 (dd, J=2.4, 0.9Hz, 1H), 7.55 (dd, J=8.7, 4.3 Hz, 1H), 7.37-7.32 (m, 1H), 3.56 (d, J=6.5Hz, 2H), 2.23-2.18 (m, 3H), 1.46 (q, J=3.8 Hz, 2H), 1.37 (dp, J=13.3,6.6 Hz, 1H), 0.84 (q, J=3.8 Hz, 2H), 0.69 (d, J=6.7 Hz, 6H). MS (ESI+)m/z 440 (M+H)⁺.

Example GI-431-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isobutoxy-5-methyl-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (55 mg, 0.288 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (35 mg, 0.288 mmol) in anhydrous dichloromethane (2 mL) wasadded to 2-methylquinoline-5-sulfonamide (53 mg, 0.24 mmol). Thereaction mixture was stirred at reflux for 24 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 8.94 (dd, J=8.8, 0.9 Hz, 1H), 8.17(dd, J=7.3, 1.3 Hz, 1H), 8.04 (dt, J=8.5, 1.0 Hz, 1H), 7.75-7.70 (m,1H), 7.70-7.67 (m, 1H), 7.41 (d, J=8.9 Hz, 1H), 7.37-7.31 (m, 1H), 3.53(d, J=6.6 Hz, 2H), 2.75 (s, 3H), 2.20 (s, 3H), 1.44 (q, J=3.8 Hz, 2H),1.33 (hept, J=6.7 Hz, 1H), 0.82 (q, J=3.9 Hz, 2H), 0.67 (d, J=6.7 Hz,6H). MS (ESI+) m/z 454 (M+H)⁺.

Example GI-44N-(1H-indole-4-sulfonyl)-1-[5-methyl-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isobutoxy-5-methyl-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (55 mg, 0.288 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (35 mg, 0.288 mmol) in anhydrous dichloromethane (2 mL) wasadded to 1H-indole-4-sulfonamide (47 mg, 0.24 mmol). The reactionmixture was stirred at reflux for 24 hours. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution, and the aqueous layerwas extracted with dichloromethane. The organic layers were combined,dried over MgSO₄, filtered and concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.71 (dd, J=2.4, 1.0 Hz, 1H), 7.59(dd, J=7.5, 0.9 Hz, 1H), 7.51 (dt, J=8.0, 0.9 Hz, 1H), 7.40-7.35 (m,1H), 7.31 (d, J=3.2 Hz, 1H), 7.11 (dd, J=8.1, 7.4 Hz, 1H), 6.84 (dd,J=3.1, 0.9 Hz, 1H), 3.81 (d, J=6.6 Hz, 2H), 2.22-2.17 (m, 3H), 1.82-1.67(m, J=6.7 Hz, 1H), 1.54 (q, J=3.8 Hz, 2H), 0.92-0.84 (m, 8H). MS (ESI+)m/z 428 (M+H)⁺.

Example GI-451-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-ethyl-2-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.228 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (52 mg, 0.273 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.273 mmol) in anhydrous dichloromethane (2 mL) wasadded to quinoline-5-sulfonamide (CAS #415913-05-2) (47 mg, 0.228 mmol).The reaction mixture was stirred at reflux for 24 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.11 (ddd, J=8.7, 1.7, 0.8 Hz, 1H),8.90 (dd, J=4.3, 1.7 Hz, 1H), 8.26 (dd, J=7.3, 1.2 Hz, 1H), 8.14 (dt,J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3 Hz, 1H), 7.75-7.69 (m, 1H),7.55 (dd, J=8.7, 4.3 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 3.58 (d, J=6.5 Hz,2H), 2.55 (q, J=7.6 Hz, 2H), 1.47 (q, J=3.8 Hz, 2H), 1.38 (dp, J=13.3,6.6 Hz, 1H), 1.19 (d, J=7.6 Hz, 3H), 0.85 (q, J=3.8 Hz, 2H), 0.69 (d,J=6.7 Hz, 6H). MS (ESI+) m/z 454 (M+H)⁺.

Example GI-461-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-ethyl-2-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.228 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (52 mg, 0.273 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.273 mmol) in anhydrous dichloromethane (2 mL) wasadded to 2-methylquinoline-5-sulfonamide (51 mg, 0.228 mmol). Thereaction mixture was stirred at reflux for 24 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 m OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 8.95 (dd, J=8.8, 0.8 Hz, 1H), 8.18(dd, J=7.3, 1.2 Hz, 1H), 8.05 (dt, J=8.5, 1.1 Hz, 1H), 7.73 (d, J=7.3Hz, 1H), 7.72-7.69 (m, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.37 (d, J=2.4 Hz,1H), 3.56 (d, J=6.5 Hz, 2H), 2.75 (s, 3H), 2.55 (q, J=7.6 Hz, 2H), 1.46(q, J=3.8 Hz, 2H), 1.34 (dp, J=13.5, 6.7 Hz, 1H), 1.20 (t, J=7.6 Hz,3H), 0.83 (q, J=3.9 Hz, 2H), 0.68 (d, J=6.7 Hz, 6H). MS (ESI+) m/z 468(M+H)⁺.

Example GI-471-[5-ethyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-ethyl-2-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.228 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (52 mg, 0.273 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.273 mmol) in anhydrous dichloromethane (2 mL) wasadded to 1H-indole-4-sulfonamide (45 mg, 0.228 mmol). The reactionmixture was stirred at reflux for 24 hours. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution, and the aqueous layerwas extracted with dichloromethane. The organic layers were combined,dried over MgSO₄, filtered and concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 m OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.71 (d, J=2.3 Hz, 1H), 7.56 (dd,J=7.4, 0.9 Hz, 1H), 7.48 (dt, J=8.1, 0.9 Hz, 1H), 7.38 (d, J=2.4 Hz,1H), 7.28 (d, J=3.1 Hz, 1H), 7.08 (dd, J=8.1, 7.5 Hz, 1H), 6.82 (dd,J=3.2, 0.9 Hz, 1H), 3.81 (d, J=6.6 Hz, 2H), 2.52 (q, J=7.6 Hz, 2H),1.81-1.66 (m, J=6.7 Hz, 1H), 1.53 (q, J=3.8 Hz, 2H), 1.18 (t, J=7.6 Hz,3H), 0.90-0.83 (m, 8H). MS (ESI+) m/z 442 (M+H)⁺.

Example GI-481-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclopropyl-2-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (60mg, 0.218 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (50 mg, 0.26 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (32 mg, 0.26 mmol) in anhydrousdichloromethane (2 mL) was added to quinoline-5-sulfonamide (CAS#415913-05-2) (45 mg, 0.218 mmol). The reaction mixture was stirred atreflux for 24 hours. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.08(ddd, J=8.7, 1.7, 0.8 Hz, 1H), 8.89 (dd, J=4.3, 1.7 Hz, 1H), 8.25 (dd,J=7.3, 1.2 Hz, 1H), 8.13 (dt, J=8.5, 1.1 Hz, 1H), 7.77 (dd, J=8.5, 7.3Hz, 1H), 7.69 (dd, J=2.4, 0.5 Hz, 1H), 7.54 (dd, J=8.7, 4.3 Hz, 1H),7.17 (d, J=2.4 Hz, 1H), 3.55 (d, J=6.6 Hz, 2H), 1.82 (tt, J=8.4, 5.1 Hz,1H), 1.44 (q, J=3.8 Hz, 2H), 1.35 (hept, J=6.7 Hz, 1H), 0.94-0.86 (m,2H), 0.82 (q, J=3.9 Hz, 2H), 0.67 (d, J=6.7 Hz, 6H), 0.64-0.58 (m, 2H).MS (ESI+) m/z 466 (M+H)⁺.

Example GI-491-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclopropyl-2-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (60mg, 0.218 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (50 mg, 0.26 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (32 mg, 0.26 mmol) in anhydrousdichloromethane (2 mL) was added to 2-methylquinoline-5-sulfonamide (48mg, 0.218 mmol). The reaction mixture was stirred at reflux for 24hours. The reaction mixture was quenched with saturated aqueous NH₄Clsolution, and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 m OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.95 (dd, J=8.8, 0.9 Hz,1H), 8.19 (dd, J=7.3, 1.2 Hz, 1H), 8.06 (dt, J=8.5, 1.1 Hz, 1H), 7.74(dd, J=8.5, 7.3 Hz, 1H), 7.71 (d, J=2.4 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H),7.19 (d, J=2.4 Hz, 1H), 3.56 (d, J=6.6 Hz, 2H), 2.77 (s, 3H), 1.85 (tt,J=8.4, 5.1 Hz, 1H), 1.46 (q, J=3.8 Hz, 2H), 1.35 (dp, J=13.3, 6.5 Hz,1H), 0.96-0.89 (m, 2H), 0.83 (q, J=3.9 Hz, 2H), 0.69 (d, J=6.7 Hz, 6H),0.66-0.60 (m, 2H). MS (ESI+) m/z 480 (M+H)⁺.

Example GI-501-[5-cyclopropyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclopropyl-2-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (60mg, 0.218 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (50 mg, 0.26 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (32 mg, 0.26 mmol) in anhydrousdichloromethane (2 mL) was added to 1H-indole-4-sulfonamide (43 mg,0.218 mmol). The reaction mixture was stirred at reflux for 24 hours.The reaction mixture was quenched with saturated aqueous NH₄Cl solution,and the aqueous layer was extracted with dichloromethane. The organiclayers were combined, dried over MgSO₄, filtered and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.70 (dd, J=2.5, 0.5 Hz, 1H), 7.57(dd, J=7.4, 0.9 Hz, 1H), 7.50 (dt, J=8.1, 0.9 Hz, 1H), 7.30 (d, J=3.2Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.10 (dd, J=8.1, 7.4 Hz, 1H), 6.81 (dd,J=3.1, 0.9 Hz, 1H), 3.78 (d, J=6.6 Hz, 2H), 1.82 (tt, J=8.4, 5.1 Hz,1H), 1.76-1.63 (m, J=6.6 Hz, 1H), 1.51 (q, J=3.8 Hz, 2H), 0.93-0.81 (m,10H), 0.66-0.55 (m, 2H). MS (ESI+) m/z 454 (M+H)⁺.

Example GI-511-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclobutyl-2-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (60mg, 0.207 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (48 mg, 0.248 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (30 mg, 0.248 mmol) inanhydrous dichloromethane (2 mL) was added to quinoline-5-sulfonamide(CAS #415913-05-2) (43 mg, 0.207 mmol). The reaction mixture was stirredat reflux for 24 hours. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.09(dt, J=8.8, 1.2 Hz, 1H), 8.89 (dt, J=4.3, 1.5 Hz, 1H), 8.27 (dt, J=7.3,1.3 Hz, 1H), 8.13 (dd, J=8.5, 1.2 Hz, 1H), 7.78 (ddd, J=8.5, 7.2, 1.1Hz, 1H), 7.74-7.69 (m, 1H), 7.54 (ddd, J=8.7, 4.3, 1.1 Hz, 1H),7.45-7.40 (m, 1H), 3.57 (dd, J=6.5, 1.1 Hz, 2H), 3.48 (p, J=8.7 Hz, 1H),2.37-2.24 (m, 2H), 2.19-1.96 (m, 3H), 1.93-1.81 (m, 1H), 1.47 (qd,J=3.8, 1.1 Hz, 2H), 1.41-1.29 (m, 2H), 0.84 (qd, J=3.9, 1.0 Hz, 2H),0.68 (dd, J=6.8, 1.1 Hz, 6H). MS (ESI+) m/z 480 (M+H)⁺.

Example GI-521-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclobutyl-2-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (60mg, 0.207 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (48 mg, 0.248 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (30 mg, 0.248 mmol) inanhydrous dichloromethane (2 mL) was added on 1H-indole-4-sulfonamide(41 mg, 0.207 mmol). The reaction mixture was stirred at reflux for 24hours. The reaction mixture was quenched with saturated aqueous NH₄Clsolution, and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 m OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.72 (dd, J=2.4, 0.8 Hz,1H), 7.60 (dd, J=7.5, 0.9 Hz, 1H), 7.51 (dt, J=8.1, 0.9 Hz, 1H), 7.45(dd, J=2.4, 0.5 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.12 (dd, J=8.1, 7.4Hz, 1H), 6.82 (dd, J=3.1, 0.9 Hz, 1H), 3.78 (d, J=6.6 Hz, 2H), 3.54-3.41(m, 1H), 2.37-2.25 (m, 2H), 2.21-1.96 (m, 3H), 1.94-1.82 (m, 1H),1.73-1.60 (m, J=6.7 Hz, 1H), 1.52 (q, J=3.9 Hz, 2H), 0.90-0.83 (m, 8H).MS (ESI+) m/z 468 (M+H)⁺.

Example GI-531-[5-cyclobutyl-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclobutyl-2-isobutoxy-3-pyridyl)cyclopropanecarboxylic acid (60mg, 0.207 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (48 mg, 0.248 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (30 mg, 0.248 mmol) inanhydrous dichloromethane (2 mL) was added to2-methylquinoline-5-sulfonamide (46 mg, 0.207 mmol). The reactionmixture was stirred at reflux for 24 hours. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution, and the aqueous layerwas extracted with dichloromethane. The organic layers were combined,dried over MgSO₄, filtered and concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound. ¹H NMR(400 MHz, methanol-d₄) δ ppm 8.80 (d, J=8.9 Hz, 1H), 8.37 (d, J=7.4 Hz,1H), 8.24 (d, J=8.4 Hz, 1H), 7.90-7.82 (m, 2H), 7.50 (d, J=8.8 Hz, 1H),7.48 (d, J=2.3 Hz, 1H), 3.52 (q, J=8.5 Hz, 1H), 3.47 (d, J=6.6 Hz, 2H),2.77 (s, 3H), 2.33 (dtd, J=10.5, 8.0, 2.5 Hz, 2H), 2.23-2.04 (m, 3H),1.95-1.83 (m, 1H), 1.42 (q, J=4.5 Hz, 2H), 1.13 (hept, J=6.7 Hz, 1H),1.06-0.98 (m, 2H), 0.62 (d, J=6.7 Hz, 6H). MS (ESI+) m/z 494 (M+H)⁺.

Example GI-541-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (103 mg, 0.56 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (38 mg, 0.31 mmol) in anhydrous dichloromethane (2 mL), and1-(6-ethyl-3-isopropoxy-2-pyridyl)cyclopropanecarboxylic acid (70 mg,0.28 mmol) was added and the mixture was stirred at ambient temperaturefor 10 minutes. 2-Methylquinoline-5-sulfonamide (65 mg, 0.28 mmol) wasadded and the reaction mixture was stirred at reflux overnight. Thereaction mixture was treated with water and organic layer was separatedon a phase separator and was concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.05 (d, J=8.8 Hz, 1H), 8.18 (dd,J=7.3, 1.2 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.70 (dd, J=8.5, 7.3 Hz,1H), 7.46 (d, J=8.9 Hz, 1H), 7.15 (d, J=8.4 Hz, 1H), 7.03 (d, J=8.4 Hz,1H), 4.32 (p, J=6.0 Hz, 1H), 2.73 (s, 3H), 2.66 (q, J=7.6 Hz, 2H), 1.51(q, J=3.9 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H), 0.99 (q, J=3.9 Hz, 2H), 0.93(d, J=6.0 Hz, 6H). MS (ESI+) m/z 454 (M+H)⁺.

Example GI-551-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (103 mg, 0.56 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (38 mg, 0.31 mmol) in anhydrous dichloromethane (2 mL),1-(6-ethyl-3-isopropoxy-2-pyridyl)cyclopropanecarboxylic acid (70 mg,0.28 mmol) was added and the mixture was stirred at ambient temperaturefor 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2) (58 mg, 0.28mmol) was added and the reaction mixture was stirred at refluxovernight. The reaction mixture was treated with water and organic layerwas separated on a phase separator and was concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.20 (ddd, J=8.7, 1.7, 0.8 Hz, 1H),8.87 (dd, J=4.3, 1.7 Hz, 1H), 8.25 (dd, J=7.3, 1.2 Hz, 1H), 8.09 (dt,J=8.5, 1.1 Hz, 1H), 7.74 (dd, J=8.5, 7.3 Hz, 1H), 7.57 (dd, J=8.7, 4.3Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.29 (hept,J=6.0 Hz, 1H), 2.63 (q, J=7.6 Hz, 2H), 1.52 (q, J=3.8 Hz, 2H), 1.21-1.10(m, 3H), 1.01 (q, J=3.8 Hz, 2H), 0.92 (d, J=6.0 Hz, 6H). MS (ESI+) m/z440 (M+H)⁺.

Example GI-561-{6-ethyl-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (103 mg, 0.56 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (38 mg, 0.31 mmol) in anhydrous dichloromethane (2 mL),1-(6-ethyl-3-isopropoxy-2-pyridyl)cyclopropanecarboxylic acid (70 mg,0.28 mmol) was added and the mixture was stirred at ambient temperaturefor 10 minutes. 1H-Indole-4-sulfonamide (55 mg, 0.28 mmol) was added andthe reaction mixture was stirred at reflux overnight. The reactionmixture was treated with water and organic layer was separated on aphase separator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.59(dd, J=7.5, 0.9 Hz, 1H), 7.47 (dt, J=8.2, 1.0 Hz, 1H), 7.28 (d, J=3.2Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.11-7.03 (m, 1H), 6.99 (d, J=8.4 Hz,1H), 6.89 (dd, J=3.2, 0.9 Hz, 1H), 4.44 (hept, J=6.0 Hz, 1H), 2.65 (q,J=7.6 Hz, 2H), 1.58 (q, J=3.9 Hz, 2H), 1.14 (d, J=6.0 Hz, 6H), 1.08-1.01(m, 5H). MS (ESI+) m/z 428 (M+H)⁺.

Example GI-571-[5-cyclobutyl-2-(4-methoxypiperidin-1-yl)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

To a suspension of1-[5-cyclobutyl-2-(4-methoxy-1-piperidyl)-3-pyridyl]cyclopropanecarboxylicacid (58 mg, 0.18 mmol) in anhydrous dichloromethane (0.7 mL), wereadded 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (44 mg, 0.26 mmol), 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.23 mmol) and 1H-indole-4-sulfonamide (35 mg, 0.18mmol). The reaction mixture was stirred at reflux overnight.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (44 mg, 0.26 mmol) and dimethyl sulfoxide (0.1 mL) wereadded and the reaction mixture was heated at reflux for 4 hours more.The reaction mixture was quenched with water (5 mL), and the aqueouslayer was extracted with dichloromethane. The organic layers werecombined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.80 (dd, J=2.4, 0.7 Hz, 1H), 7.59(dd, J=7.4, 0.9 Hz, 1H), 7.52 (dd, J=2.4, 0.6 Hz, 1H), 7.49 (dt, J=8.2,0.9 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.10 (dd, J=8.1, 7.5 Hz, 1H), 6.86(dd, J=3.1, 0.9 Hz, 1H), 3.43 (td, J=8.9, 7.4 Hz, 1H), 3.35 (dd, J=12.8,4.1 Hz, 2H), 3.31 (s, 3H), 3.20 (tt, J=8.6, 4.0 Hz, 1H), 2.71 (ddd,J=12.8, 9.9, 2.9 Hz, 2H), 2.34-2.22 (m, 2H), 2.17-1.97 (m, 3H),1.91-1.79 (m, 1H), 1.73-1.62 (m, 2H), 1.56 (q, J=3.6 Hz, 2H), 1.39 (dtd,J=12.8, 9.4, 3.6 Hz, 2H), 0.97 (q, J=3.7 Hz, 2H). MS (ESI+) m/z 509(M+H)⁺.

Example GI-581-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isopropoxy-5-methyl-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.255 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (59 mg, 0.306 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (37 mg, 0.306 mmol) in anhydrous dichloromethane (2 mL) wasadded to 2-methylquinoline-5-sulfonamide (56 mg, 0.255 mmol). Thereaction mixture was stirred at reflux for 4 hours. The reaction mixturewas quenched with saturated aqueous NH₄Cl solution, and the aqueouslayer was extracted with dichloromethane. The organic layers werecombined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 m OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.02 (dd, J=8.9, 0.9 Hz, 1H), 8.16(dd, J=7.3, 1.2 Hz, 1H), 8.01 (dt, J=8.5, 1.1 Hz, 1H), 7.73-7.68 (m,1H), 7.67 (dd, J=2.4, 0.8 Hz, 1H), 7.44 (d, J=8.9 Hz, 1H), 7.29 (dd,J=2.4, 0.7 Hz, 1H), 4.86 (h, J=6.1 Hz, 5H), 2.72 (s, 3H), 2.17 (d, J=0.7Hz, 3H), 1.44 (q, J=3.9 Hz, 2H), 0.90 (d, J=6.1 Hz, 6H), 0.80 (q, J=3.9Hz, 2H). MS (ESI+) m/z 440 (M+H)⁺.

Example GI-59N-(1H-indole-4-sulfonyl)-1-{5-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isopropoxy-5-methyl-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.255 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (59 mg, 0.306 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (37 mg, 0.306 mmol) in anhydrous dichloromethane (2 mL) wasadded to 1H-indole-4-sulfonamide (56 mg, 0.255 mmol). The reactionmixture was stirred at reflux for 4 hours. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution, and the aqueous layerwas extracted with dichloromethane. The organic layers were combined,dried over MgSO₄, filtered and concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.68 (dd, J=2.5, 1.0 Hz, 1H), 7.59(dd, J=7.4, 0.9 Hz, 1H), 7.45 (dt, J=8.2, 0.9 Hz, 1H), 7.35-7.24 (m,2H), 7.07 (dd, J=8.1, 7.4 Hz, 1H), 6.88 (dd, J=3.2, 0.9 Hz, 1H), 5.06(hept, J=6.1 Hz, 1H), 2.17-2.13 (m, 3H), 1.15 (d, J=6.1 Hz, 6H), 1.07(t, J=7.3 Hz, 2H), 0.85 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 414 (M+H)⁺.

Example GI-601-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclopropyl-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (60mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (53 mg, 0.276 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (34 mg, 0.276 mmol) inanhydrous dichloromethane (2 mL) was added to2-methylquinoline-5-sulfonamide (51 mg, 0.23 mmol). The reaction mixturewas stirred at reflux for 4 hours. The reaction mixture was quenchedwith saturated aqueous NH₄Cl solution, and the aqueous layer wasextracted with dichloromethane. The organic layers were combined, driedover MgSO₄, filtered and concentrated. The crude material was purifiedby reverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm,flow rate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1%diethylamine to give the title compound. ¹H NMR (400 MHz, methanol-d₄) δppm 9.00 (dd, J=8.8, 0.9 Hz, 1H), 8.15 (dd, J=7.3, 1.2 Hz, 1H), 8.02(dt, J=8.5, 1.1 Hz, 1H), 7.75-7.65 (m, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.13(d, J=2.5 Hz, 1H), 4.92-4.82 (m, 1H), 2.73 (s, 3H), 1.80 (tt, J=8.4, 5.1Hz, 1H), 1.44 (q, J=3.9 Hz, 2H), 0.98-0.84 (m, 8H), 0.79 (q, J=3.9 Hz,2H), 0.62-0.52 (m, 2H). MS (ESI+) m/z 466 (M+H)⁺.

Example GI-611-{5-cyclopropyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclopropyl-2-isopropoxy-3-pyridyl)cyclopropanecarboxylic acid (60mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (53 mg, 0.276 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (34 mg, 0.276 mmol) inanhydrous dichloromethane (2 mL) was added to 1H-indole-4-sulfonamide(51 mg, 0.23 mmol). The reaction mixture was stirred at reflux for 4hours. The reaction mixture was quenched with saturated aqueous NH₄Clsolution, and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.72 (dd, J=2.4, 0.5 Hz,1H), 7.59 (dd, J=7.5, 0.9 Hz, 1H), 7.50 (dt, J=8.1, 0.9 Hz, 1H), 7.31(d, J=3.2 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 7.12 (dd, J=8.1, 7.4 Hz, 1H),6.88 (dd, J=3.2, 0.9 Hz, 1H), 5.06 (hept, J=6.1 Hz, 1H), 1.83 (tt,J=8.5, 5.2 Hz, 1H), 1.51 (q, J=3.8 Hz, 2H), 1.18-1.09 (m, 6H), 0.97-0.86(m, 2H), 0.84 (q, J=3.9 Hz, 2H), 0.66-0.56 (m, 2H). MS (ESI+) m/z 440(M+H)⁺.

Example GI-621-{2-[(propan-2-yl)oxy]-5-(pyrrolidin-1-yl)pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isopropoxy-5-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(70 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (55 mg, 0.288 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (35 mg, 0.288 mmol) inanhydrous dichloromethane (2 mL) was added to quinoline-5-sulfonamide(CAS #415913-05-2) (50 mg, 0.24 mmol). The reaction mixture was stirredat reflux overnight. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.18(ddd, J=8.7, 1.7, 0.9 Hz, 1H), 8.88 (dd, J=4.3, 1.7 Hz, 1H), 8.27 (dd,J=7.3, 1.2 Hz, 1H), 8.12 (dt, J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3Hz, 1H), 7.57 (dd, J=8.8, 4.3 Hz, 1H), 7.22 (d, J=3.0 Hz, 1H), 6.92 (d,J=3.0 Hz, 1H), 4.75 (h, J=6.1 Hz, 1H), 3.24-3.16 (m, 4H), 2.03-1.97 (m,4H), 1.46 (q, J=3.8 Hz, 2H), 0.89 (d, J=6.1 Hz, 6H), 0.85 (q, J=3.9 Hz,2H). MS (ESI+) m/z 481 (M+H)⁺.

Example GI-63N-(2-methylquinoline-5-sulfonyl)-1-{2-[(propan-2-yl)oxy]-5-(pyrrolidin-1-yl)pyridin-3-yl}cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isopropoxy-5-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(70 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (55 mg, 0.288 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (35 mg, 0.288 mmol) inanhydrous dichloromethane (2 mL) was added on2-methylquinoline-5-sulfonamide (53 mg, 0.24 mmol). The reaction mixturewas stirred at reflux overnight. The reaction mixture was quenched withsaturated aqueous NH₄Cl solution, and the aqueous layer was extractedwith dichloromethane. The organic layers were combined, dried overMgSO₄, filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.04(dd, J=8.8, 0.8 Hz, 1H), 8.18 (dd, J=7.3, 1.2 Hz, 1H), 8.04 (dt, J=8.5,1.1 Hz, 1H), 7.72 (dd, J=8.5, 7.3 Hz, 1H), 7.45 (d, J=8.9 Hz, 1H), 7.23(d, J=3.0 Hz, 1H), 6.92 (d, J=3.0 Hz, 1H), 4.77 (h, J=6.1 Hz, 1H),3.24-3.16 (m, 4H), 2.74 (s, 3H), 2.07-1.95 (m, 4H), 1.46 (q, J=3.8 Hz,2H), 0.90 (d, J=6.1 Hz, 6H), 0.86 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 495(M+H)⁺.

Example GI-64N-(1H-indole-4-sulfonyl)-1-{2-[(propan-2-yl)oxy]-5-(pyrrolidin-1-yl)pyridin-3-yl}cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isopropoxy-5-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(70 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (55 mg, 0.288 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (35 mg, 0.288 mmol) inanhydrous dichloromethane (2 mL) was added on 1H-indole-4-sulfonamide(47 mg, 0.24 mmol). The reaction mixture was stirred at reflux for 4hours. The reaction mixture was quenched with saturated aqueous NH₄Clsolution, and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 m OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.64 (dd, J=7.5, 0.9 Hz,1H), 7.52 (dt, J=8.1, 0.9 Hz, 1H), 7.32 (d, J=3.1 Hz, 1H), 7.26 (d,J=3.0 Hz, 1H), 7.13 (t, J=7.8 Hz, 1H), 6.97 (d, J=3.0 Hz, 1H), 6.89 (dd,J=3.1, 0.9 Hz, 1H), 5.20 (s, 1H), 4.59 (s, 2H), 3.50-3.41 (m, 1H),3.23-3.19 (m, 4H), 3.16 (s, 3H), 3.13 (d, J=7.2 Hz, 1H), 3.10 (s, 2H),2.07-1.97 (m, 5H), 1.97-1.87 (m, 1H), 1.49 (q, J=3.9 Hz, 2H), 1.15-1.05(m, 8H), 0.88 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 469 (M+H)⁺.

Example GI-651-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (92 mg, 0.48 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.26 mmol) in anhydrous dichloromethane (2 mL),1-(2,5-diisopropoxy-3-pyridyl)cyclopropanecarboxylic acid (69 mg, 0.24mmol) was added and the mixture was stirred at ambient temperature for10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2) (54 mg, 0.24mmol) was added and the reaction mixture was stirred at refluxovernight. The reaction mixture was treated with water. The organiclayer was separated on a phase separator and was concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.16 (ddd, J=8.7, 1.7, 0.9 Hz, 1H),8.88 (dd, J=4.3, 1.7 Hz, 1H), 8.25 (dd, J=7.3, 1.3 Hz, 1H), 8.13 (dt,J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3 Hz, 1H), 7.57 (dd, J=8.7, 4.3Hz, 1H), 7.53 (d, J=3.0 Hz, 1H), 7.12 (d, J=3.0 Hz, 1H), 4.92-4.78 (m,1H), 4.41 (hept, J=6.1 Hz, 1H), 1.45 (q, J=3.9 Hz, 2H), 1.26 (d, J=6.1Hz, 6H), 0.92 (d, J=6.1 Hz, 6H), 0.84 (q, J=3.9 Hz, 2H). MS (ESI+) m/z470 (M+H)⁺.

Example GI-661-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (92 mg, 0.48 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (32 mg, 0.26 mmol) in anhydrous dichloromethane (2 mL),1-(2,5-diisopropoxy-3-pyridyl)cyclopropanecarboxylic acid (69 mg, 0.24mmol) was added and the mixture was stirred at ambient temperature for10 minutes. 1H-Indole-4-sulfonamide (51 mg, 0.24 mmol) was added and thereaction mixture was stirred at reflux overnight. The reaction wastreated with water. The organic layer was separated on a phase separatorand was concentrated. The crude material was purified by reverse-phaseHPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to givethe title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.60 (d, J=7.4Hz, 1H), 7.55 (d, J=2.9 Hz, 1H), 7.52-7.48 (m, 1H), 7.31 (d, J=3.1 Hz,1H), 7.16 (d, J=2.9 Hz, 1H), 7.11 (t, J=7.7 Hz, 1H), 6.91-6.86 (m, 1H),5.02 (dq, J=12.3, 6.2 Hz, 3H), 4.43 (hept, J=5.9, 5.5 Hz, 1H), 3.30 (s,1H), 1.51 (q, J=3.8 Hz, 2H), 1.28 (d, J=6.1, 6H), 1.19-1.09 (m, 6H),0.86 (q, J=3.8 Hz, 2H). MS (ESI+) m/z 458 (M+H)⁺.

Example GI-671-{2,5-bis[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (92 mg, 0.48 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (32 mg, 0.26 mmol) in anhydrousdichloromethane (2 mL),1-(2,5-diisopropoxy-3-pyridyl)cyclopropanecarboxylic acid (69 mg, 0.24mmol) was added and the mixture was stirred at ambient temperature for10 minutes. 2-Methylquinoline-5-sulfonamide (58 mg, 0.24 mmol) was addedand the reaction mixture was stirred at reflux overnight. The reactionwas treated with water. The organic layer was separated on a phaseseparator and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.91(dd, J=8.8, 0.9 Hz, 1H), 8.05 (dd, J=7.3, 1.2 Hz, 1H), 7.92 (dt, J=8.4,1.1 Hz, 1H), 7.60 (dd, J=8.5, 7.3 Hz, 1H), 7.42 (d, J=2.9 Hz, 1H), 7.34(d, J=8.9 Hz, 1H), 7.00 (d, J=3.0 Hz, 1H), 4.83-4.66 (m, 1H), 4.30(hept, J=6.1 Hz, 1H), 2.62 (s, 3H), 1.35 (q, J=3.9 Hz, 2H), 1.15 (d,J=6.1 Hz, 6H), 0.81 (d, J=6.1 Hz, 6H), 0.72 (q, J=3.9 Hz, 2H). MS (ESI+)m/z 484 (M+H)⁺.

Example GI-681-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isobutoxy-5-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(44 mg, 0.144 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (363 mg, 0.173 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (21 mg, 0.173 mmol) inanhydrous dichloromethane (2 mL) was added to quinoline-5-sulfonamide(CAS #415913-05-2) (30 mg, 0.144 mmol). The reaction mixture was stirredat reflux overnight. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.97(dd, J=4.3, 1.5 Hz, 1H), 8.93 (d, J=8.7 Hz, 1H), 8.44 (dd, J=7.4, 1.2Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 7.90 (dd, J=8.5, 7.4 Hz, 1H), 7.61 (dd,J=8.7, 4.3 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 6.96 (d, J=2.9 Hz, 1H), 3.41(d, J=6.6 Hz, 2H), 3.24 (h, J=3.6 Hz, 4H), 2.08-1.95 (m, 4H), 1.40 (q,J=4.3 Hz, 2H), 1.18-1.08 (m, 1H), 1.01 (q, J=3.6, 2.9 Hz, 2H), 0.61 (d,J=6.7 Hz, 6H). MS (ESI+) m/z 495 (M+H)⁺.

Example GI-691-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isobutoxy-5-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(44 mg, 0.144 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (363 mg, 0.173 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (21 mg, 0.173 mmol) inanhydrous dichloromethane (2 mL) was added to2-methylquinoline-5-sulfonamide (32 mg, 0.144 mmol). The reactionmixture was stirred at reflux overnight. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution, and the aqueous layerwas extracted with dichloromethane. The organic layers were combined,dried over MgSO₄, filtered and concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 8.94 (dd, J=8.8, 0.8 Hz, 1H), 8.18(dd, J=7.3, 1.2 Hz, 1H), 8.03 (dt, J=8.5, 1.1 Hz, 1H), 7.71 (dd, J=8.5,7.3 Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.19 (d, J=2.9 Hz, 1H), 6.96 (d,J=3.0 Hz, 1H), 3.48 (d, J=6.6 Hz, 2H), 3.25-3.17 (m, 4H), 2.74 (s, 3H),2.06-1.95 (m, 4H), 1.44 (q, J=3.8 Hz, 2H), 1.32 (dq, J=13.3, 6.7 Hz,1H), 0.83 (q, J=3.8 Hz, 2H), 0.66 (d, J=6.7 Hz, 6H). MS (ESI+) m/z 509(M+H)⁺

Example GI-70N-(1H-indole-4-sulfonyl)-1-[2-(2-methylpropoxy)-5-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-isobutoxy-5-pyrrolidin-1-yl-3-pyridyl)cyclopropanecarboxylic acid(44 mg, 0.144 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (363 mg, 0.173 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (21 mg, 0.173 mmol) inanhydrous dichloromethane (2 mL) was added to 1H-indole-4-sulfonamide(32 mg, 0.144 mmol). The reaction mixture was stirred at refluxovernight. The reaction mixture was quenched with saturated aqueousNH₄Cl solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.59(dd, J=7.4, 0.9 Hz, 1H), 7.49 (dt, J=8.1, 1.0 Hz, 1H), 7.28 (d, J=3.1Hz, 1H), 7.20 (d, J=2.9 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.98 (d, J=3.0Hz, 1H), 6.83 (dd, J=3.1, 0.9 Hz, 1H), 3.72 (d, J=6.6 Hz, 2H), 3.24-3.16(m, 4H), 2.04-1.93 (m, 4H), 1.68 (dh, J=13.7, 6.9 Hz, 1H), 1.50 (q,J=3.8 Hz, 2H), 0.90-0.82 (m, 8H). MS (ESI+) m/z 483 (M+H)⁺.

Example GI-711-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-(dimethylamino)-2-isopropoxy-3-pyridyl]cyclopropanecarboxylic acid(41 mg, 0.155 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (36 mg, 0.186 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (23 mg, 0.186 mmol) inanhydrous dichloromethane (2 mL) was added to quinoline-5-sulfonamide(CAS #415913-05-2) (32 mg, 0.155 mmol). The reaction mixture was stirredat reflux overnight. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.17(ddd, J=8.7, 1.7, 0.8 Hz, 1H), 8.87 (dd, J=4.3, 1.7 Hz, 1H), 8.25 (dd,J=7.3, 1.2 Hz, 1H), 8.11 (dt, J=8.5, 1.1 Hz, 1H), 7.77 (dd, J=8.5, 7.3Hz, 1H), 7.57 (dd, J=8.7, 4.3 Hz, 1H), 7.42 (d, J=3.1 Hz, 1H), 7.14 (d,J=3.0 Hz, 1H), 4.79 (h, J=6.1 Hz, 1H), 2.81 (s, 6H), 1.46 (q, J=3.8 Hz,2H), 0.89 (d, J=6.1 Hz, 6H), 0.84 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 455(M+H)⁺.

Example GI-721-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-(dimethylamino)-2-isopropoxy-3-pyridyl]cyclopropanecarboxylic acid(41 mg, 0.155 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (36 mg, 0.186 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (23 mg, 0.186 mmol) inanhydrous dichloromethane (2 mL) was added to2-methylquinoline-5-sulfonamide (32 mg, 0.155 mmol). The reactionmixture was stirred at reflux overnight. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution, and the aqueous layerwas extracted with dichloromethane. The organic layers were combined,dried over MgSO₄, filtered and concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.02 (dd, J=8.8, 0.9 Hz, 1H), 8.17(dd, J=7.3, 1.2 Hz, 1H), 8.01 (dt, J=8.5, 1.0 Hz, 1H), 7.70 (dd, J=8.5,7.3 Hz, 1H), 7.47-7.38 (m, 2H), 7.13 (d, J=3.1 Hz, 1H), 4.79 (p, J=6.1Hz, 2H), 2.80 (s, 6H), 2.73 (s, 3H), 1.44 (q, J=3.8 Hz, 2H), 0.88 (d,J=6.1 Hz, 6H), 0.82 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 469 (M+H)⁺.

Example GI-731-{5-(dimethylamino)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-(dimethylamino)-2-isopropoxy-3-pyridyl]cyclopropanecarboxylic acid(41 mg, 0.155 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (36 mg, 0.186 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (23 mg, 0.186 mmol) inanhydrous dichloromethane (2 mL) was added to 1H-indole-4-sulfonamide(32 mg, 0.155 mmol). The reaction mixture was stirred at refluxovernight. The reaction mixture was quenched with saturated aqueousNH₄Cl solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 Mm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.60(dd, J=7.4, 0.9 Hz, 1H), 7.49 (dt, J=8.2, 0.9 Hz, 1H), 7.43 (d, J=3.0Hz, 1H), 7.29 (d, J=3.1 Hz, 1H), 7.18 (d, J=3.1 Hz, 1H), 7.10 (dd,J=8.2, 7.4 Hz, 1H), 6.89 (dd, J=3.1, 0.9 Hz, 1H), 4.97 (h, J=6.1 Hz,1H), 2.82 (s, 6H), 1.50 (q, J=3.9 Hz, 2H), 1.18 (t, J=7.3 Hz, 6H), 1.12(d, J=6.1 Hz, 6H), 0.85 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 443 (M+H)⁺.

Example GI-741-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (96 mg, 0.50 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.27 mmol) in anhydrous dichloromethane (2 mL),1-(2-isobutoxy-5-methoxy-3-pyridyl)cyclopropanecarboxylic acid (63 mg,0.25 mmol) was added and the mixture was stirred at ambient temperaturefor 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2) (52 mg, 0.25mmol) was added and the reaction mixture was stirred at refluxovernight. The reaction was treated with water. The organic layer wasseparated on a phase separator and was concentrated. The crude materialwas purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.18 (ddd, J=8.7, 1.7, 0.9 Hz, 1H),8.90 (dd, J=4.3, 1.7 Hz, 1H), 8.26 (dd, J=7.3, 1.2 Hz, 1H), 8.13 (dt,J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3 Hz, 1H), 7.61-7.54 (m, 2H),7.14 (d, J=3.0 Hz, 1H), 4.85 (h, J=6.1 Hz, 1H), 3.77 (s, 3H), 1.47 (q,J=3.9 Hz, 2H), 0.92 (d, J=6.2 Hz, 6H), 0.85 (q, J=3.9 Hz, 2H). MS (ESI+)m/z 442 (M+H)⁺.

Example GI-75N-(1H-indole-4-sulfonyl)-1-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (96 mg, 0.50 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.27 mmol) in anhydrous dichloromethane (2 mL),1-(2-isobutoxy-5-methoxy-3-pyridyl)cyclopropanecarboxylic acid (63 mg,0.25 mmol) was added and the mixture was stirred at ambient temperaturefor 10 minutes. 1H-Indole-4-sulfonamide (49 mg, 0.25 mmol) was added andthe reaction mixture was stirred at reflux overnight. The reaction wastreated with water. The organic layer was separated on a phase separatorand concentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 m OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.61 (dd, J=7.4, 0.9 Hz,1H), 7.55 (d, J=3.0 Hz, 1H), 7.47 (dt, J=8.1, 0.9 Hz, 1H), 7.30 (d,J=3.1 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.09 (t, J=7.8 Hz, 1H), 6.90 (dd,J=3.1, 0.9 Hz, 1H), 5.04 (hept, J=6.1 Hz, 1H), 3.74 (s, 3H), 1.53 (q,J=3.9 Hz, 2H), 1.17 (d, J=6.2 Hz, 6H), 0.88 (q, J=3.9 Hz, 2H). MS (ESI+)m/z 430 (M+H)⁺.

Example GI-761-{5-methoxy-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (96 mg, 0.50 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.27 mmol) in anhydrous dichloromethane (2 mL),1-(2-isobutoxy-5-methoxy-3-pyridyl)cyclopropanecarboxylic acid (63 mg,0.25 mmol) was added and the mixture was stirred at ambient temperaturefor 10 minutes. 2-Methylquinoline-5-sulfonamide (56 mg, 0.25 mmol) wasadded and the reaction mixture was stirred at reflux overnight. Thereaction was treated with water. The organic layer was separated on aphase separator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.02(dd, J=8.8, 0.8 Hz, 1H), 8.16 (dd, J=7.3, 1.2 Hz, 1H), 8.02 (dt, J=8.5,1.1 Hz, 1H), 7.70 (dd, J=8.5, 7.3 Hz, 1H), 7.54 (d, J=3.0 Hz, 1H), 7.44(d, J=8.8 Hz, 1H), 7.12 (d, J=3.0 Hz, 1H), 4.84 (h, J=6.1 Hz, 4H), 3.75(s, 3H), 2.72 (s, 3H), 1.45 (q, J=3.9 Hz, 2H), 0.90 (d, J=6.2 Hz, 6H),0.83 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 456 (M+H)⁺.

Example GI-771-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (134 mg, 0.70 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (47 mg, 0.38 mmol) in anhydrous dichloromethane (2 mL),1-(2-isobutoxy-5-methoxy-3-pyridyl)cyclopropanecarboxylic acid (93 mg,0.35 mmol) was added and the mixture was stirred at ambient temperaturefor 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2) (72 mg, 0.35mmol) was added and the reaction mixture was stirred at refluxovernight. The reaction was treated with water. The organic layer wasseparated on a phase separator and was concentrated. The crude materialwas purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 8.89-8.82 (m, 2H), 8.22 (d, J=7.3Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 7.83-7.75 (m, 1H), 7.57-7.49 (m, 2H),7.20 (d, J=4.4 Hz, 1H), 3.78 (s, 3H), 3.27 (d, J=6.5 Hz, 2H), 1.37 (d,J=6.2 Hz, 2H), 0.97 (dt, J=13.3, 6.6 Hz, 1H), 0.79-0.75 (m, 2H), 0.48(d, J=6.8 Hz, 6H). MS (ESI+) m/z 456 (M+H)⁺.

Example GI-78N-(1H-indole-4-sulfonyl)-1-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (134 mg, 0.70 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (47 mg, 0.38 mmol) in anhydrous dichloromethane (2 mL),1-(2-isobutoxy-5-methoxy-3-pyridyl)cyclopropanecarboxylic acid (93 mg,0.35 mmol) was added and the mixture was stirred at ambient temperaturefor 10 minutes. 1H-Indole-4-sulfonamide (68 mg, 0.35 mmol) was added andthe reaction mixture was stirred at reflux overnight. The reaction wastreated with water. The organic layer was separated on a phase separatorand was concentrated. The crude material was purified by reverse-phaseHPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flow rate 50mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to givethe title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.57 (dd, J=7.4,0.9 Hz, 1H), 7.54 (d, J=3.0 Hz, 1H), 7.48 (dt, J=8.1, 1.0 Hz, 1H), 7.28(d, J=3.2 Hz, 1H), 7.19 (d, J=3.0 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 6.83(dd, J=3.2, 0.9 Hz, 1H), 3.80 (d, J=6.6 Hz, 2H), 3.74 (s, 3H), 1.82-1.69(m, J=6.7 Hz, 1H), 1.53 (q, J=3.8 Hz, 2H), 0.92-0.84 (m, 8H). MS (ESI+)m/z 444 (M+H)⁺.

Example GI-791-[5-methoxy-2-(2-methylpropoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (134 mg, 0.70 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (47 mg, 0.38 mmol) in anhydrous dichloromethane (2 mL)1-(2-isobutoxy-5-methoxy-3-pyridyl)cyclopropanecarboxylic acid (93 mg,0.35 mmol) was added and the mixture was stirred at ambient temperaturefor 10 minutes. 2-Methylquinoline-5-sulfonamide (77 mg, 0.35 mmol) wasadded and the reaction mixture was stirred at reflux overnight. Thereaction mixture was treated with water. The organic layer was separatedon a phase separator and was concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 8.94 (dd, J=8.8, 0.8 Hz, 1H), 8.17(dd, J=7.3, 1.2 Hz, 1H), 8.04 (dt, J=8.5, 1.1 Hz, 1H), 7.71 (dd, J=8.5,7.3 Hz, 1H), 7.54 (d, J=3.0 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.16 (d,J=3.0 Hz, 1H), 3.77 (s, 3H), 3.53 (d, J=6.6 Hz, 2H), 2.74 (s, 3H), 1.44(q, J=3.9 Hz, 2H), 1.35 (dp, J=13.3, 6.6 Hz, 1H), 0.84 (q, J=3.9 Hz,2H), 0.68 (d, J=6.7 Hz, 6H). MS (ESI+) m/z 470 (M+H)⁺.

Example GI-801-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-isopropoxy-6-methyl-3-pyridyl)cyclopropanecarboxylic acid (80 mg,0.34 mmol) in anhydrous dichloromethane (3 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (130 mg, 0.68 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (42 mg, 0.34 mmol) were added, followed byquinoline-5-sulfonamide (CAS #415913-05-2) (64 mg, 0.306 mmol). Thereaction mixture was stirred at reflux for 2 hours. The reaction mixturewas quenched with saturated aqueous NH₄Cl solution. The organic layerwas separated on a phase separator and was concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, chloroform-d) δ ppm 8.97 (dd, J=4.2, 1.6 Hz, 1H), 8.81(ddd, J=8.7, 1.6, 0.9 Hz, 1H), 8.47 (dd, J=7.5, 1.3 Hz, 1H), 8.35 (d,J=8.5 Hz, 1H), 7.81 (t, J=8.0 Hz, 1H), 7.45 (dd, J=8.8, 4.2 Hz, 1H),7.25 (d, J=7.3 Hz, 1H), 6.64-6.57 (m, 1H), 5.38 (p, J=6.1 Hz, 1H), 2.41(s, 3H), 1.43 (q, J=4.3 Hz, 2H), 1.31-1.24 (m, 7H), 0.90 (q, J=4.3 Hz,2H). MS (ESI+) m/z 426 (M+H)⁺.

Example GI-811-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-(2-isopropoxy-6-methyl-3-pyridyl)cyclopropanecarboxylic acid (80 mg,0.34 mmol) in anhydrous dichloromethane (3 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (130 mg, 0.68 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (42 mg, 0.34 mmol) were added, followed by2-methylquinoline-5-sulfonamide (68 mg, 0.306 mmol). The reactionmixture was stirred at reflux for 2 hours. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution. The organic layer wasseparated on a phase separator and concentrated. The crude material waspurified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBD column,30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound. ¹H NMR(400 MHz, chloroform-d) δ ppm 8.70 (dd, J=8.8, 0.9 Hz, 1H), 8.39 (dd,J=7.5, 1.2 Hz, 1H), 8.27 (dt, J=8.5, 1.1 Hz, 1H), 7.77 (dd, J=8.5, 7.5Hz, 1H), 7.34 (d, J=8.9 Hz, 1H), 7.29 (d, J=7.4 Hz, 2H), 6.67 (dd,J=7.4, 0.7 Hz, 1H), 5.42 (hept, J=6.2 Hz, 1H), 2.76 (s, 3H), 2.47 (s,3H), 1.48-1.41 (m, 2H), 1.30 (d, J=6.2 Hz, 6H), 0.95-0.87 (m, 2H). MS(ESI+) m/z 440 (M+H)⁺.

Example GI-82N-(1H-indole-4-sulfonyl)-1-{6-methyl-2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide

To a solution of1-(2-isopropoxy-6-methyl-3-pyridyl)cyclopropanecarboxylic acid (80 mg,0.34 mmol) in anhydrous dichloromethane (3 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (130 mg, 0.68 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (42 mg, 0.34 mmol) were added, followed by1H-indole-4-sulfonamide (60 mg, 0.306 mmol). The reaction mixture wasstirred at reflux for 2 hours. The reaction mixture was quenched withsaturated aqueous NH₄Cl solution. The organic layer was separated on aphase separator and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.61 (s,1H), 8.50 (s, 1H), 7.88 (dd, J=7.6, 0.9 Hz, 1H), 7.60 (dt, J=8.1, 0.9Hz, 1H), 7.37-7.31 (m, 2H), 7.26 (d, J=15.8 Hz, 1H), 6.84 (ddd, J=3.2,2.0, 0.9 Hz, 1H), 6.72-6.66 (m, 1H), 5.41 (hept, J=6.2 Hz, 1H), 2.46 (s,3H), 1.47 (q, J=4.2 Hz, 2H), 1.30 (d, J=6.2 Hz, 6H), 0.91 (q, J=4.3 Hz,2H). MS (ESI+) m/z 414 (M+H)⁺.

Example GI-831-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-(azetidin-1-yl)-2-isopropoxy-3-pyridyl]cyclopropanecarboxylic acid(60 mg, 0.217 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (50 mg, 0.26 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (32 mg, 0.26 mmol) in anhydrousdichloromethane (2 mL) was added on quinoline-5-sulfonamide (CAS#415913-05-2) (45 mg, 0.217 mmol). The reaction mixture was stirred atreflux for 3 hours. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound with N,N-dimethylaminopyridine. The compoundwas dissolved in ethyl acetate and washed with saturated aqueous NH₄Clsolution (3 times), dried over Na₂SO₄, filtered and concentrated to givethe title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.06 (ddd,J=8.8, 1.6, 0.9 Hz, 1H), 8.99 (dd, J=4.3, 1.6 Hz, 1H), 8.47 (dd, J=7.5,1.2 Hz, 1H), 8.34 (dt, J=8.5, 1.1 Hz, 1H), 7.93 (dd, J=8.5, 7.4 Hz, 1H),7.66 (dd, J=8.8, 4.3 Hz, 1H), 7.31 (d, J=2.9 Hz, 1H), 6.80 (d, J=2.9 Hz,1H), 4.92 ((h, J=6.1 Hz, 1H), 3.86 (t, J=7.2 Hz, 4H), 2.45-2.34 (m, 2H),1.39-1.31 (m, 2H), 1.04-0.96 (m, 8H). MS (ESI+) m/z 467 (M+H)⁺.

Example GI-841-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-(azetidin-1-yl)-2-isopropoxy-3-pyridyl]cyclopropanecarboxylic acid(60 mg, 0.217 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (50 mg, 0.26 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (32 mg, 0.26 mmol) in anhydrousdichloromethane (2 mL) was added to 2-methylquinoline-5-sulfonamide (48mg, 0.217 mmol). The reaction mixture was stirred at reflux for 3 hours.The reaction mixture was quenched with saturated aqueous NH₄Cl solution,and the aqueous layer was extracted with dichloromethane. The organiclayers were combined, dried over MgSO₄, filtered and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compoundwith N,N-dimethylaminopyridine. The compound was dissolved in ethylacetate and washed with saturated aqueous NH₄Cl solution (3 times),dried over Na₂SO₄, filtered and concentrated to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 8.96-8.89 (m, 1H), 8.37 (dd, J=7.5,1.2 Hz, 1H), 8.24 (dt, J=8.5, 1.1 Hz, 1H), 7.87 (dd, J=8.5, 7.5 Hz, 1H),7.55 (d, J=8.9 Hz, 1H), 7.31 (d, J=2.9 Hz, 1H), 6.80 (d, J=2.9 Hz, 1H),4.92 ((h, J=6.1 Hz, 1H), 3.86 (t, J=7.2 Hz, 4H), 2.78 (s, 3H), 2.45-2.34(m, 2H), 1.40-1.32 (m, 2H), 1.01 (d, J=6.2 Hz, 8H). MS (ESI+) m/z 481(M+H)⁺.

Example GI-851-{5-(azetidin-1-yl)-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-(azetidin-1-yl)-2-isopropoxy-3-pyridyl]cyclopropanecarboxylic acid(60 mg, 0.217 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (50 mg, 0.26 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (32 mg, 0.26 mmol) in anhydrousdichloromethane (2 mL) was added on 1H-indole-4-sulfonamide (42 mg,0.217 mmol). The reaction mixture was stirred at reflux for 3 hours. Thereaction mixture was quenched with saturated aqueous NH₄Cl solution, andthe aqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compoundwith N,N-dimethylaminopyridine. The compound was dissolved in ethylacetate and washed with saturated aqueous NH₄Cl solution (3 times),dried over Na₂SO₄, filtered and concentrated to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.76 (dd, J=7.6, 0.9 Hz, 1H), 7.70(dt, J=8.2, 1.0 Hz, 1H), 7.44 (d, J=3.2 Hz, 1H), 7.32 (d, J=2.9 Hz, 1H),7.24 (t, J=7.9 Hz, 1H), 6.84-6.76 (m, 2H), 5.04 (p, J=6.1 Hz, 1H), 3.85(t, J=7.2 Hz, 4H), 2.39 (p, J=7.2 Hz, 2H), 1.41-1.33 (m, 2H), 1.12 (d,J=6.1 Hz, 6H), 0.98 (q, J=4.5 Hz, 2H). MS (ESI+) m/z 455 (M+H)⁺.

Example GI-861-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (53 mg, 0.28 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (18 mg, 0.15 mmol) in anhydrous dichloromethane (2 mL),1-(6-isobutoxy-3-isopropoxy-2-pyridyl)cyclopropanecarboxylic acid (41mg, 0.14 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(29 mg, 0.14 mmol) was added and the reaction mixture was stirred atreflux overnight. The reaction mixture was quenched with aqueous HCl(1N, 280 μL, 0.28 mmol) and water. The organic layer was separated on aphase separator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.23(ddd, J=8.8, 1.7, 0.9 Hz, 1H), 8.88 (dd, J=4.3, 1.6 Hz, 1H), 8.31 (dd,J=7.3, 1.3 Hz, 1H), 8.12 (dt, J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3Hz, 1H), 7.59 (dd, J=8.7, 4.3 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 6.52 (d,J=8.7 Hz, 1H), 4.16 (hept, J=6.1 Hz, 1H), 3.91 (d, J=6.6 Hz, 2H),2.09-1.95 (m, 1H), 1.42 (q, J=3.8 Hz, 2H), 1.04 (q, J=3.8 Hz, 2H), 1.00(d, J=6.8 Hz, 6H), 0.86 (d, J=6.0 Hz, 6H). MS (ESI+) m/z 484 (M+H)⁺.

Example GI-871-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (134 mg, 0.70 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (47 mg, 0.38 mmol) in anhydrous dichloromethane (2 mL),1-[2-(cyclopropylmethoxy)-5-methoxy-3-pyridyl]cyclopropanecarboxylicacid (92 mg, 0.35 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(72 mg, 0.35 mmol) was added and the reaction mixture was stirred atreflux overnight. The reaction mixture was quenched with aqueous HCl(1N, 700 μL, 0.70 mmol) and water. The organic layer was separated on aphase separator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.10 (ddd,J=8.7, 1.7, 0.9 Hz, 1H), 8.86 (dd, J=4.3, 1.7 Hz, 1H), 8.28 (dd, J=7.3,1.2 Hz, 1H), 8.11 (dt, J=8.5, 1.1 Hz, 1H), 7.77 (dd, J=8.5, 7.3 Hz, 1H),7.58-7.50 (m, 2H), 7.16 (d, J=3.0 Hz, 1H), 3.78 (s, 3H), 3.69 (d, J=6.3Hz, 2H), 1.41 (q, J=3.9 Hz, 2H), 0.82 (q, J=3.9 Hz, 2H), 0.74-0.62 (m,1H), 0.27-0.16 (m, 2H), −0.01-0.03 (m, 2H). MS (ESI+) m/z 454 (M+H)⁺.

Example GI-881-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (134 mg, 0.70 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (47 mg, 0.38 mmol) in anhydrous dichloromethane (2 mL),1-[2-(cyclopropylmethoxy)-5-methoxy-3-pyridyl]cyclopropanecarboxylicacid (92 mg, 0.35 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1H-Indole-4-sulfonamide (68 mg, 0.35 mmol)was added and the reaction mixture was stirred at reflux overnight. Thereaction mixture was quenched with aqueous HCl (1N, 700 μL, 0.70 mmol)and water. The organic layer was separated on a phase separator andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 m OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% formic acid/acetonitrile+0.1% formic acid to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.63 (dd, J=7.5, 0.9 Hz,1H), 7.54 (d, J=3.0 Hz, 1H), 7.49 (dt, J=8.1, 1.0 Hz, 1H), 7.29 (d,J=3.1 Hz, 1H), 7.19 (d, J=3.0 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.85 (dd,J=3.2, 0.9 Hz, 1H), 3.89 (d, J=6.6 Hz, 2H), 3.78 (s, 3H), 1.49 (q, J=3.9Hz, 2H), 1.01-0.89 (m, 1H), 0.86 (q, J=3.9 Hz, 2H), 0.43-0.32 (m, 2H),0.18 (dt, J=6.1, 4.4 Hz, 2H). MS (ESI+) m/z 442 (M+H)⁺.

Example GI-89N-(1H-indole-4-sulfonyl)-1-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (53 mg, 0.28 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (18 mg, 0.15 mmol) in anhydrous dichloromethane (2 mL,1-(6-isobutoxy-3-isopropoxy-2-pyridyl)cyclopropanecarboxylic acid (41mg, 0.14 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1H-Indole-4-sulfonamide (27 mg, 0.14 mmol)was added and the reaction mixture was stirred at reflux overnight. Thereaction mixture was quenched with aqueous HCl (1N, 280 μL, 0.28 mmol)and water. The organic layer was separated on a phase separator andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.69 (d, J=7.4 Hz, 1H),7.54 (d, J=8.1 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H),7.15 (t, J=7.8 Hz, 1H), 6.92 (dd, J=3.2, 0.9 Hz, 1H), 6.57 (d, J=8.7 Hz,1H), 4.32 (hept, J=6.1 Hz, 1H), 3.95 (d, J=6.6 Hz, 2H), 2.11-1.96 (m,1H), 1.45-1.40 (m, 2H), 1.13-1.09 (m, 2H), 1.08 (d, J=6.1 Hz, 6H), 1.01(d, J=6.7 Hz, 6H). MS (ESI+) m/z 472 (M+H)⁺.

Example GI-901-{6-(2-methylpropoxy)-3-[(propan-2-yl)oxy]pyridin-2-yl}-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (53 mg, 0.28 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (18 mg, 0.15 mmol) in anhydrous dichloromethane (2 mL),1-(6-isobutoxyd-3-isopropoxy-2-pyridyl)cyclopropanecarboxylic acid (41mg, 0.14 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 2-Methylquinoline-5-sulfonamide (31 mg, 0.14mmol) was added and the reaction mixture was stirred at refluxovernight. The reaction mixture was quenched with aqueous HCl (1N, 280μL, 0.28 mmol) and water. The organic layer was separated on a phaseseparator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.10(dd, J=8.9, 0.9 Hz, 1H), 8.23 (dd, J=7.3, 1.3 Hz, 1H), 8.03 (dt, J=8.4,1.0 Hz, 1H), 7.72 (dd, J=8.5, 7.3 Hz, 1H), 7.48 (d, J=8.9 Hz, 1H), 7.14(d, J=8.8 Hz, 1H), 6.52 (d, J=8.8 Hz, 1H), 4.18 (hept, J=6.0 Hz, 1H),3.91 (d, J=6.6 Hz, 2H), 2.75 (s, 3H), 2.08-1.95 (m, 1H), 1.42 (q, J=3.8Hz, 2H), 1.04 (q, J=3.8 Hz, 2H), 1.00 (d, J=6.7 Hz, 6H), 0.88 (d, J=6.0Hz, 6H). MS (ESI+) m/z 498 (M+H)⁺.

Example GI-911-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (77 mg, 0.40 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (26 mg, 0.22 mmol) in anhydrous dichloromethane (2 mL),1-[5-(cyclopropylmethoxy)-2-methoxy-4-pyridyl]cyclopropanecarboxylicacid (53 mg, 0.20) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(42 mg, 0.20 mmol) was added and the reaction mixture was stirred atreflux overnight. The reaction mixture was quenched with aqueous HCl 1N(400 μL, 0.4 mmol) and water. The organic layer was separated on a phaseseparator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the compound with impurities. The residue was purified by flashchromatography on silica gel (10 g ultra Biotage®) eluting with agradient of 0-3% methanol in dichloromethane to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 9.03-8.96 (m, 2H), 8.47 (dd, J=7.5,1.2 Hz, 1H), 8.35 (d, J=8.5 Hz, 1H), 7.93 (dd, J=8.5, 7.4 Hz, 1H), 7.67(dd, J=8.7, 4.4 Hz, 1H), 7.58 (s, 1H), 6.66 (s, 1H), 5.49 (s, 1H), 3.87(s, 3H), 3.41 (d, J=6.4 Hz, 2H), 1.39 (q, J=4.5 Hz, 2H), 1.06 (q, J=4.5Hz, 2H), 0.30-0.19 (m, 2H), −0.05-0.02 (m, 2H). MS (ESI+) m/z 454(M+H)⁺.

Example GI-921-[2-(cyclopropylmethoxy)-5-methoxypyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (134 mg, 0.70 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (47 mg, 0.38 mmol) in anhydrous dichloromethane (2 mL),1-[2-(cyclopropylmethoxy)-5-methoxy-3-pyridyl]cyclopropanecarboxylicacid (92 mg, 0.35 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 2-Methylquinoline-5-sulfonamide (77 mg, 0.35mmol) was added and the reaction mixture was stirred at refluxovernight. The reaction mixture was quenched with aqueous HCl (1N, 700μL, 0.70 mmol) and water. The organic layer was separated on a phaseseparator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.84 (d, J=8.9Hz, 1H), 8.22 (d, J=7.9 Hz, 2H), 7.87 (t, J=7.9 Hz, 1H), 7.75 (d, J=3.0Hz, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.20 (d, J=3.0 Hz, 1H), 3.78 (s, 3H),3.76 (d, J=6.4 Hz, 2H), 2.71 (s, 3H), 1.27 (q, J=4.3 Hz, 2H), 1.02 (s,2H), 0.76-0.64 (m, 1H), 0.26-0.19 (m, 2H), −0.02-0.07 (m, 2H). MS (ESI+)m/z 468 (M+H)⁺.

Example GI-931-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (77 mg, 0.40 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (26 mg, 0.22 mmol) in anhydrous dichloromethane (2 mL),1-[5-(cyclopropylmethoxy)-2-methoxy-4-pyridyl]cyclopropanecarboxylicacid (53 mg, 0.20) was added and the mixture was stirred at ambienttemperature for 10 minutes. 2-Methylquinoline-5-sulfonamide (44 mg, 0.20mmol) was added and the reaction mixture was stirred at refluxovernight. The reaction mixture was quenched with aqueous HCl (1N, 400μL, 0.4 mmol) and water. The organic layer was separated on a phaseseparator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the compound with NN-dimethylaminopyridine. The residue waswashed with saturated aqueous NH₄Cl solution and extracted with ethylacetate. The organic layer was separated, dried over Na₂SO₄, filteredand concentrated to give the title compound. ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.03-8.96 (m, 2H), 8.47 (dd, J=7.5, 1.2 Hz, 1H), 8.35(d, J=8.5 Hz, 1H), 7.93 (dd, J=8.5, 7.4 Hz, 1H), 7.67 (dd, J=8.7, 4.4Hz, 1H), 7.58 (s, 1H), 6.66 (s, 1H), 5.49 (s, 1H), 3.87 (s, 3H), 3.41(d, J=6.4 Hz, 2H), 1.39 (q, J=4.5 Hz, 2H), 1.06 (q, J=4.5 Hz, 2H),0.30-0.19 (m, 2H), −0.05-0.02 (m, 2H). MS (ESI+) m/z 454 (M+H)⁺.

Example GI-941-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (115 mg, 0.60 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (40 mg, 0.33 mmol) in anhydrous dichloromethane (2 mL),1-[5-cyclobutyl-2-(2-methoxyethoxy)-3-pyridyl]cyclopropanecarboxylicacid (87 mg, 0.30 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 2-Methylquinoline-5-sulfonamide (66 mg, 0.30mmol) was added and the reaction mixture was stirred at reflux for 2hours. The reaction mixture was quenched with aqueous HCl (1N, 600 μL,0.60 mmol) and water. The organic layer was separated on a phaseseparator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.93(d, J=8.8 Hz, 1H), 8.16 (dd, J=7.4, 1.2 Hz, 1H), 8.11 (dt, J=8.5, 1.1Hz, 1H), 7.80 (dd, J=2.4, 0.8 Hz, 1H), 7.64 (dd, J=8.5, 7.3 Hz, 1H),7.32 (d, J=8.8 Hz, 1H), 7.25 (d, J=2.4 Hz, 4H), 4.34-4.27 (m, 2H),3.61-3.54 (m, 2H), 3.39 (d, J=8.2 Hz, 1H), 3.35 (s, 3H), 2.75 (s, 3H),2.31-2.20 (m, 2H), 2.07-1.94 (m, 3H), 1.88-1.78 (m, 1H), 1.51 (q, J=3.9Hz, 2H), 0.89 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 496 (M+H)⁺.

Example GI-951-[5-(cyclopropylmethoxy)-2-methoxypyridin-4-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (96 mg, 0.50 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.27 mmol) in anhydrous dichloromethane (2 mL),1-[5-(cyclopropylmethoxy)-2-methoxy-4-pyridyl]cyclopropanecarboxylicacid (66 mg, 0.25) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1H-Indol-4-sulfonamide (49 mg, 0.25 mmol)was added and the reaction mixture was stirred at reflux overnight. Thereaction mixture was quenched with aqueous HCl (1N, 400 μL, 0.4 mmol)and water. The organic layer was separated on a phase separator and wasconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.61 (dd, J=7.4, 0.9 Hz,1H), 7.53 (s, 1H), 7.48 (dt, J=8.1, 0.9 Hz, 1H), 7.28 (d, J=3.1 Hz, 1H),7.10 (t, J=7.8 Hz, 1H), 6.83 (dd, J=3.1, 0.9 Hz, 1H), 6.63 (s, 1H), 3.80(s, 3H), 3.61 (d, J=6.5 Hz, 2H), 1.47 (q, J=4.0 Hz, 2H), 0.92-0.80 (m,3H), 0.41-0.30 (m, 2H), 0.19-0.11 (m, 2H). MS (ESI+) m/z 442 (M+H)⁺.

Example GI-961-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (96 mg, 0.50 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.27 mmol) in anhydrous dichloromethane (2 mL),1-[2-(cyclopropylmethoxy)-5-methyl-3-pyridyl]cyclopropanecarboxylic acid(62 mg, 0.25 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(52 mg, 0.25 mmol) was added and the reaction mixture was stirred atreflux for 2 hours. The reaction mixture was quenched with aqueous HCl(1N, 500 μL, 0.50 mmol) and water. The organic layer was separated on aphase separator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.11(ddd, J=8.7, 1.7, 0.9 Hz, 1H), 8.86 (dd, J=4.3, 1.7 Hz, 1H), 8.28 (dd,J=7.4, 1.3 Hz, 1H), 8.11 (dt, J=8.5, 1.1 Hz, 1H), 7.78 (dd, J=8.5, 7.3Hz, 1H), 7.68 (dd, J=2.4, 0.9 Hz, 1H), 7.54 (dd, J=8.7, 4.3 Hz, 1H),7.33 (dd, J=2.4, 0.6 Hz, 1H), 3.70 (d, J=6.3 Hz, 2H), 2.20 (t, J=0.7 Hz,3H), 1.41 (q, J=3.9 Hz, 2H), 0.80 (q, J=3.9 Hz, 2H), 0.74-0.62 (m, 1H),0.27-0.16 (m, 2H), 0.06-−0.04 (m, 2H). MS (ESI+) m/z 438 (M+H)⁺.

Example GI-971-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (96 mg, 0.50 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.27 mmol) in anhydrous dichloromethane (2 mL),1-[2-(cyclopropylmethoxy)-5-methyl-3-pyridyl]cyclopropanecarboxylic acid(62 mg, 0.25 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1H-Indole-4-sulfonamide (49 mg, 0.25 mmol)was added and the reaction mixture was stirred at reflux for 2 hours.The reaction mixture was quenched with aqueous HCl (1N, 500 μL, 0.50mmol) and water. The organic layer was separated on a phase separatorand was concentrated. The crude material was purified by reverse-phaseHPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to givethe title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.68 (dd, J=2.4,1.0 Hz, 1H), 7.62 (dd, J=7.5, 0.9 Hz, 1H), 7.49 (dt, J=8.1, 1.0 Hz, 1H),7.38-7.33 (m, 1H), 7.29 (d, J=3.2 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.83(dd, J=3.1, 0.9 Hz, 1H), 3.89 (d, J=6.6 Hz, 2H), 2.20 (d, J=0.7 Hz, 3H),1.48 (q, J=3.9 Hz, 2H), 1.00-0.88 (m, 1H), 0.84 (q, J=3.9 Hz, 2H),0.42-0.32 (m, 2H), 0.22-0.14 (m, 2H). MS (ESI+) m/z 426 (M+H)⁺.

Example GI-981-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (88 mg, 0.46 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (30 mg, 0.25 mmol) in anhydrous dichloromethane (2 mL),1-[5-cyclobutyl-2-(cyclopropylmethoxy)-3-pyridyl]cyclopropanecarboxylicacid (66 mg, 0.23 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1H-Indole-4-sulfonamide (45 mg, 0.23 mmol)was added and the reaction mixture was stirred at reflux for 2 hours.The reaction mixture was quenched with aqueous HCl (1N, 460 μL, 0.46mmol) and water. The organic layer was separated on a phase separatorand was concentrated. The crude material was purified by reverse-phaseHPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to givethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.51 (s, 1H),7.96 (dd, J=2.4, 0.7 Hz, 1H), 7.89 (dd, J=7.6, 0.9 Hz, 1H), 7.62 (dt,J=8.0, 0.9 Hz, 1H), 7.37 (dd, J=2.4, 0.6 Hz, 1H), 7.34 (t, J=2.9 Hz,1H), 7.29 (t, J=7.9 Hz, 1H), 6.83 (ddd, J=3.2, 2.1, 0.9 Hz, 1H), 4.10(d, J=7.0 Hz, 2H), 3.46 (p, J=8.5 Hz, 1H), 2.40-2.29 (m, 2H), 2.15-2.05(m, 2H), 1.92-1.82 (m, 2H), 1.54 (q, J=4.2 Hz, 2H), 1.10-1.01 (m, 1H),0.97 (q, J=4.3 Hz, 2H), 0.51-0.42 (m, 2H), 0.22 (dt, J=6.1, 4.6 Hz, 2H).MS (ESI+) m/z 466 (M+H)⁺.

Example GI-991-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (115 mg, 0.60 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (40 mg, 0.33 mmol) in anhydrous dichloromethane (2 mL),1-[5-cyclobutyl-2-(2-methoxyethoxy)-3-pyridyl]cyclopropanecarboxylicacid (87 mg, 0.30 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1H-Indole-4-sulfonamide (58 mg, 0.30 mmol)was added and the reaction mixture was stirred at reflux for 2 hours.The reaction mixture was quenched with aqueous HCl (1N, 600 μL, 0.60mmol) and water. The organic layer was separated on a phase separatorand was concentrated. The crude material was purified by reverse-phaseHPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to givethe title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.73 (dd, J=2.4,0.7 Hz, 1H), 7.62 (dd, J=7.4, 0.9 Hz, 1H), 7.51 (dt, J=8.1, 0.9 Hz, 1H),7.43 (dd, J=2.4, 0.6 Hz, 1H), 7.29 (d, J=3.1 Hz, 1H), 7.13 (t, J=7.8 Hz,1H), 6.81 (dd, J=3.1, 0.9 Hz, 1H), 4.17-4.05 (m, 2H), 3.47 (p, J=8.5 Hz,1H), 3.37-3.33 (m, 2H), 3.27 (s, 3H), 2.31 (dtd, J=10.5, 8.0, 2.4 Hz,2H), 2.21-1.95 (m, 3H), 1.93-1.81 (m, 1H), 1.47 (q, J=3.9 Hz, 2H), 0.85(q, J=3.9 Hz, 2H). MS (ESI+) m/z 470 (M+H)⁺.

Example GI-1001-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (88 mg, 0.46 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (30 mg, 0.25 mmol) in anhydrous dichloromethane (2 mL),1-[5-cyclobutyl-2-(cyclopropylmethoxy)-3-pyridyl]cyclopropanecarboxylicacid (66 mg, 0.23 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(48 mg, 0.23 mmol) was added and the reaction mixture was stirred atreflux for 2 hours. The reaction mixture was quenched with aqueous HCl(1N, 460 μL, 0.46 mmol) and water. The organic layer was separated on aphase separator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.99(d, J=8.7 Hz, 1H), 8.95 (dd, J=4.2, 1.7 Hz, 1H), 8.26 (ddd, J=16.8, 7.8,1.2 Hz, 2H), 7.82 (dd, J=2.4, 0.8 Hz, 1H), 7.71 (dd, J=8.5, 7.3 Hz, 1H),7.43 (dd, J=8.7, 4.2 Hz, 1H), 7.27 (d, J=2.4 Hz, 8H), 3.98 (d, J=6.5 Hz,2H), 3.39 (p, J=9.0 Hz, 1H), 2.32-2.22 (m, 3H), 2.02-1.94 (m, 2H), 1.84(dd, J=7.5, 5.4 Hz, 1H), 1.50 (q, J=3.9 Hz, 2H), 1.04-0.94 (m, 1H),0.94-0.89 (m, 2H), 0.44-0.33 (m, 2H), 0.20 (dt, J=6.1, 4.5 Hz, 2H). MS(ESI+) m/z 478 (M+H)⁺.

Example GI-1011-[2-(cyclopropylmethoxy)-5-methylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (96 mg, 0.50 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (33 mg, 0.27 mmol) in anhydrous dichloromethane (2 mL),1-[2-(cyclopropylmethoxy)-5-methyl-3-pyridyl]cyclopropanecarboxylic acid(62 mg, 0.25 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 2-Methylquinoline-5-sulfonamide (56 mg, 0.25mmol) was added and the reaction mixture was stirred at reflux for 2hours. The reaction mixture was quenched with aqueous HCl (1N, 500 μL,0.50 mmol) and water. The organic layer was separated on a phaseseparator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.96(dd, J=8.8, 0.9 Hz, 1H), 8.20 (dd, J=7.4, 1.2 Hz, 1H), 8.03 (dt, J=8.5,1.1 Hz, 1H), 7.76-7.65 (m, 2H), 7.42 (d, J=8.9 Hz, 1H), 7.33 (dd, J=2.4,0.6 Hz, 1H), 3.70 (d, J=6.3 Hz, 2H), 2.73 (s, 3H), 2.20 (t, J=0.7 Hz,3H), 1.41 (q, J=3.9 Hz, 2H), 0.80 (q, J=3.9 Hz, 2H), 0.71-0.59 (m, 1H),0.27-0.16 (m, 2H), 0.05-−0.04 (m, 2H). MS (ESI+) m/z 452 (M+H)⁺.

Example GI-1021-(5-ethyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-ethyl-2-(4-isopropoxy-1-piperidyl)-3-pyridyl]cyclopropanecarboxylicacid (60 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (42 mg, 0.22 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (27 mg, 0.22 mmol) in anhydrousdichloromethane (2 mL) was added to 1H-indole-4-sulfonamide (35 mg, 0.18mmol). The reaction mixture was stirred at reflux for 3.5 hours. Thereaction mixture was quenched with saturated aqueous NH₄Cl solution, andthe aqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 m OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.82 (d, J=2.4 Hz, 1H), 7.60 (dd,J=7.4, 0.9 Hz, 1H), 7.54-7.47 (m, 2H), 7.31 (d, J=3.2 Hz, 1H), 7.11 (t,J=7.8 Hz, 1H), 6.87 (dd, J=3.1, 0.9 Hz, 1H), 3.74 (hept, J=6.1 Hz, 1H),3.40 (dq, J=13.3, 4.3 Hz, 3H), 2.71 (ddd, J=13.0, 10.3, 2.7 Hz, 2H),2.54 (q, J=7.6 Hz, 2H), 1.70-1.60 (m, 2H), 1.58 (q, J=3.6 Hz, 2H), 1.43(dtd, J=13.0, 9.8, 3.6 Hz, 2H), 1.23-1.12 (m, 9H), 0.99 (q, J=3.7 Hz,2H). MS (ESI+) m/z 511 (M+H)⁺.

Example GI-1041-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-cyclobutyl-2-(4-isopropoxy-1-piperidyl)-3-pyridyl]cyclopropanecarboxylicacid (60 mg, 0.167 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (38 mg, 0.20 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (24 mg, 0.20 mmol) in anhydrousdichloromethane (2 mL) was added to 1H-indole-4-sulfonamide (33 mg,0.167 mmol). The reaction mixture was stirred at reflux for 72 hours.The reaction mixture was quenched with saturated aqueous NH₄Cl solution,and the aqueous layer was extracted with dichloromethane. The organiclayers were combined, dried over MgSO₄, filtered and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5μm OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 7.80 (d, J=2.4 Hz, 1H), 7.61 (dd,J=7.5, 0.9 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.30(d, J=3.1 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.87 (dd, J=3.2, 0.9 Hz, 1H),3.73 (hept, J=6.1 Hz, 1H), 3.52-3.34 (m, 4H), 2.70 (ddd, J=13.0, 10.4,2.7 Hz, 2H), 2.29 (pt, J=10.1, 4.4 Hz, 2H), 2.19-1.95 (m, 3H), 1.92-1.81(m, 1H), 1.64 (dd, J=13.2, 3.9 Hz, 2H), 1.57 (q, J=3.6 Hz, 2H), 1.42(qd, J=9.6, 4.9 Hz, 2H), 1.15 (d, J=6.1 Hz, 6H), 0.97 (q, J=3.7 Hz, 2H).MS (ESI+) m/z 537 (M+H)⁺.

Example GI-1051-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-cyclobutyl-2-(4-isopropoxy-1-piperidyl)-3-pyridyl]cyclopropanecarboxylicacid (60 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (42 mg, 0.22 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (27 mg, 0.22 mmol) in anhydrousdichloromethane (2 mL) was added to quinoline-5-sulfonamide (CAS#415913-05-2) (35 mg, 0.18 mmol). The reaction mixture was stirred atreflux for 3.5 hours. The reaction mixture was quenched with saturatedaqueous NH₄Cl solution, and the aqueous layer was extracted withdichloromethane. The organic layers were combined, dried over MgSO₄,filtered and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.19(ddd, J=8.7, 1.6, 0.8 Hz, 1H), 8.88 (dd, J=4.3, 1.7 Hz, 1H), 8.27 (dd,J=7.3, 1.2 Hz, 1H), 8.12 (dt, J=8.5, 1.1 Hz, 1H), 7.83-7.74 (m, 2H),7.57 (dd, J=8.7, 4.2 Hz, 1H), 7.48 (dd, J=2.4, 0.6 Hz, 1H), 3.68 (hept,J=6.1 Hz, 1H), 3.50-3.38 (m, 1H), 3.35 (dt, J=8.8, 4.2 Hz, 1H),3.30-3.22 (m, 2H), 2.62 (ddd, J=12.9, 10.1, 2.7 Hz, 2H), 2.34-2.21 (m,2H), 2.14-1.94 (m, 3H), 1.91-1.79 (m, 1H), 1.56-1.45 (m, 4H), 1.38-1.27(m, 2H), 1.13 (d, J=6.1 Hz, 6H), 0.96 (q, J=3.8 Hz, 2H). MS (ESI+) m/z549 (M+H)⁺.

Example GI-1061-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (115 mg, 0.60 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (40 mg, 0.33 mmol) in anhydrous dichloromethane (2 mL),1-[5-ethyl-2-(2-methoxyethoxy)-3-pyridyl]cyclopropanecarboxylic acid (78mg, 0.30 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(62 mg, 0.30 mmol) was added and the reaction mixture was stirred atreflux for 2 hours. The reaction mixture was quenched with aqueous HCl(1N, 600 μL, 0.60 mmol) and water. The organic layer was separated on aphase separator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 9.03(ddd, J=8.7, 1.7, 0.8 Hz, 1H), 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.28-8.18(m, 2H), 7.79 (d, J=2.3 Hz, 1H), 7.69 (dd, J=8.5, 7.3 Hz, 1H), 7.44 (dd,J=8.7, 4.2 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 3.94 (d, J=6.5 Hz, 2H), 2.48(q, J=7.6 Hz, 2H), 1.49 (q, J=3.9 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H),1.00-0.92 (m, 1H), 0.90 (q, J=3.9 Hz, 2H), 0.41-0.30 (m, 2H), 0.18 (dt,J=6.2, 4.5 Hz, 2H). MS (ESI+) m/z 452 (M+H)⁺.

Example GI-1071-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (115 mg, 0.60 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (40 mg, 0.33 mmol) in anhydrous dichloromethane (2 mL),1-[5-ethyl-2-(2-methoxyethoxy)-3-pyridyl]cyclopropanecarboxylic acid (78mg, 0.30 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 2-Methylquinoline-5-sulfonamide (66 mg, 0.30mmol) was added and the reaction mixture was stirred at reflux for 2hours. The reaction mixture was quenched with aqueous HCl (1N, 600 μL,0.60 mmol) and water. The organic layer was separated on a phaseseparator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.93(dd, J=8.8, 0.8 Hz, 1H), 8.15 (dd, J=7.3, 1.2 Hz, 1H), 8.11 (dt, J=8.5,1.1 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 7.63 (dd, J=8.5, 7.3 Hz, 1H), 7.32(d, J=8.9 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 3.92 (d, J=6.4 Hz, 2H), 2.75(s, 3H), 2.48 (q, J=7.6 Hz, 2H), 1.49 (q, J=3.8 Hz, 2H), 1.13 (t, J=7.6Hz, 3H), 0.96-0.90 (m, 1H), 0.89 (q, J=3.8 Hz, 2H), 0.39-0.28 (m, 2H),0.16 (dt, J=6.1, 4.4 Hz, 2H). MS (ESI+) m/z 466 (M+H)⁺.

Example GI-1081-[2-(cyclopropylmethoxy)-5-ethylpyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (115 mg, 0.60 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (40 mg, 0.33 mmol) in anhydrous dichloromethane (2 mL),1-[5-ethyl-2-(2-methoxyethoxy)-3-pyridyl]cyclopropanecarboxylic acid (78mg, 0.30 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1H-Indole-4-sulfonamide (58 mg, 0.30 mmol)was added and the reaction mixture was stirred at reflux for 2 hours.The reaction mixture was quenched with aqueous HCl (1N, 600 μL, 0.60mmol) and water. The organic layer was separated on a phase separatorand was concentrated. The crude material was purified by reverse-phaseHPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to givethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.49 (s, 1H),7.96 (d, J=2.4 Hz, 1H), 7.90 (dd, J=7.6, 0.9 Hz, 1H), 7.63 (dt, J=8.1,1.0 Hz, 1H), 7.37-7.32 (m, 2H), 7.30 (t, J=7.9 Hz, 1H), 6.83 (ddd,J=3.2, 2.1, 1.0 Hz, 1H), 4.10 (d, J=6.9 Hz, 2H), 2.57 (q, J=7.6 Hz, 2H),1.53 (q, J=4.2 Hz, 2H), 1.23 (t, J=7.6 Hz, 3H), 1.09-1.02 (m, 1H), 0.96(q, J=4.3 Hz, 2H), 0.52-0.43 (m, 2H), 0.26-0.18 (m, 2H). MS (ESI+) m/z440 (M+H)⁺.

Example GI-1091-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (118 mg, 0.62 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (41 mg, 0.34 mmol) in anhydrous dichloromethane (2 mL),1-[5-ethyl-2-(2-methoxyethoxy)-3-pyridyl]cyclopropanecarboxylic acid (82mg, 0.31 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 1H-Indole-4-sulfonamide (60 mg, 0.31 mmol)was added and the reaction mixture was stirred at reflux for 2 hours.The reaction mixture was quenched with aqueous HCl (1N, 620 μL, 0.62mmol) and water. The organic layer was separated on a phase separatorand was concentrated. The crude material was purified by reverse-phaseHPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to givethe title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.54 (s, 1H),7.93 (d, J=2.4 Hz, 1H), 7.85 (dd, J=7.6, 0.9 Hz, 1H), 7.59 (dt, J=8.2,1.0 Hz, 1H), 7.36-7.22 (m, 7H), 6.86 (ddd, J=3.1, 2.1, 1.0 Hz, 1H),4.39-4.32 (m, 2H), 3.53-3.46 (m, 2H), 3.30 (s, 3H), 2.56 (q, J=7.6 Hz,2H), 1.54 (q, J=4.2 Hz, 2H), 1.21 (t, J=7.6 Hz, 3H), 0.96 (q, J=4.2 Hz,2H). MS (ESI+) m/z 444 (M+H)⁺.

Example GI-1101-[5-cyclobutyl-2-(cyclopropylmethoxy)pyridin-3-yl]-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (88 mg, 0.46 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (30 mg, 0.25 mmol) in anhydrous dichloromethane (2 mL),1-[5-cyclobutyl-2-(cyclopropylmethoxy)-3-pyridyl]cyclopropanecarboxylicacid (66 mg, 0.23 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. 2-Methylquinoline-5-sulfonamide (51 mg, 0.23mmol) was added and the reaction mixture was stirred at reflux for 2hours. The reaction mixture was quenched with aqueous HCl (1N, 460 μL,0.46 mmol) and water. The organic layer was separated on a phaseseparator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm8.92-8.86 (m, 1H), 8.18 (dd, J=7.3, 1.2 Hz, 1H), 8.13 (dt, J=8.5, 1.1Hz, 1H), 7.81 (dd, J=2.4, 0.7 Hz, 1H), 7.65 (dd, J=8.5, 7.3 Hz, 1H),7.32 (d, J=8.8 Hz, 1H), 7.27 (d, J=0.5 Hz, 1H), 3.96 (d, J=6.4 Hz, 2H),3.39 (p, J=9.0 Hz, 1H), 2.75 (s, 3H), 2.31-2.21 (m, 2H), 2.04-1.94 (m,3H), 1.88-1.80 (m, 1H), 1.50 (q, J=3.9 Hz, 2H), 1.00-0.93 (m, 1H), 0.91(q, J=4.0 Hz, 2H), 0.42-0.31 (m, 2H), 0.18 (dt, J=6.2, 4.5 Hz, 2H). MS(ESI+) m/z 492 (M+H)⁺.

Example GI-1111-[5-cyclobutyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (115 mg, 0.60 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (40 mg, 0.33 mmol) in anhydrous dichloromethane (2 mL),1-[5-cyclobutyl-2-(2-methoxyethoxy)-3-pyridyl]cyclopropanecarboxylicacid (87 mg, 0.30 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(62 mg, 0.30 mmol) was added and the reaction mixture was stirred atreflux for 2 hours. The reaction mixture was quenched with aqueous HCl(1N, 600 μL, 0.60 mmol) and water. The organic layer was separated on aphase separator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm9.10-9.02 (m, 1H), 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.27-8.17 (m, 2H), 7.80(d, J=2.3 Hz, 1H), 7.69 (dd, J=8.5, 7.3 Hz, 1H), 7.44 (dd, J=8.7, 4.2Hz, 1H), 7.25 (d, J=2.4 Hz, 1H), 4.36-4.29 (m, 2H), 3.65-3.58 (m, 2H),3.44-3.31 (m, 4H), 2.32-2.20 (m, 2H), 2.02-1.93 (m, 3H), 1.88-1.78 (m,1H), 1.52 (q, J=3.9 Hz, 2H), 0.90 (q, J=3.9 Hz, 2H). MS (ESI+) m/z 482(M+H)⁺.

Example GI-1121-[5-ethyl-2-(2-methoxyethoxy)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (118 mg, 0.62 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (41 mg, 0.34 mmol) in anhydrous dichloromethane (2 mL),1-[5-ethyl-2-(2-methoxyethoxy)-3-pyridyl]cyclopropanecarboxylic acid (82mg, 0.31 mmol) was added and the mixture was stirred at ambienttemperature for 10 minutes. Quinoline-5-sulfonamide (CAS #415913-05-2)(64 mg, 0.31 mmol) was added and the reaction mixture was stirred atreflux for 2 hours. The reaction mixture was quenched with aqueous HCl(1N, 620 μL, 0.62 mmol) and water. The organic layer was separated on aphase separator and was concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamineto give the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm9.09-9.03 (m, 1H), 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.24 (dd, J=7.3, 1.3Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.80 (d, J=2.3 Hz, 1H), 7.69 (dd,J=8.5, 7.3 Hz, 1H), 7.44 (dd, J=8.7, 4.2 Hz, 1H), 7.22 (d, J=2.4 Hz,1H), 4.37-4.30 (m, 2H), 3.67-3.60 (m, 2H), 3.38 (s, 3H), 2.48 (q, J=7.6Hz, 2H), 1.52 (q, J=3.9 Hz, 2H), 1.14 (t, J=7.6 Hz, 3H), 0.90 (q, J=4.0Hz, 2H). MS (ESI+) m/z 456 (M+H)⁺.

Example GI-1131-(5-cyclobutyl-2-{4-[(propan-2-yl)oxy]piperidin-1-yl}pyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-[5-cyclobutyl-2-(4-isopropoxy-1-piperidyl)-3-pyridyl]cyclopropanecarboxylicacid (60 mg, 0.18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (CAS #25952-53-8) (42 mg, 0.22 mmol) and4-dimethylaminopyridine (CAS #1122-58-3) (27 mg, 0.22 mmol) in anhydrousdichloromethane (2 mL) was added to 2-methylquinoline-5-sulfonamide (37mg, 0.18 mmol). The reaction mixture was stirred at reflux for 3.5hours. The reaction mixture was quenched with saturated aqueous NH₄Clsolution, and the aqueous layer was extracted with dichloromethane. Theorganic layers were combined, dried over MgSO₄, filtered andconcentrated. The crude material was purified by reverse-phase HPLCWaters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 50 mL/minute,H₂O+0.1% diethylamine/acetonitrile+0.1% diethylamine to give the titlecompound. ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.06 (dd, J=8.8, 0.8 Hz,1H), 8.21 (dd, J=7.3, 1.2 Hz, 1H), 8.04 (dt, J=8.5, 1.1 Hz, 1H), 7.81(dd, J=2.4, 0.7 Hz, 1H), 7.73 (dd, J=8.5, 7.3 Hz, 1H), 7.50 (dd, J=2.4,0.6 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 3.70 (hept, J=6.1 Hz, 1H),3.52-3.40 (m, 1H), 3.37 (dd, J=9.0, 4.2 Hz, 1H), 3.31-3.23 (m, 2H), 2.75(s, 3H), 2.63 (ddd, J=12.9, 10.2, 2.7 Hz, 2H), 2.30 (dddt, J=8.2, 6.7,5.3, 3.3 Hz, 2H), 2.16-1.99 (m, 3H), 1.93-1.81 (m, 1H), 1.57-1.47 (m,4H), 1.40-1.30 (m, 2H), 1.14 (d, J=6.1 Hz, 6H), 0.97 (q, J=3.7 Hz, 2H).MS (ESI+) m/z 563 (M+H)⁺.

Example GI-1141-(5-cyclobutyl-2-ethoxypyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclobutyl-2-ethoxy-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (53 mg, 0.276 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (34 mg, 0.276 mmol) in anhydrous dichloromethane (2 mL) wasadded to quinoline-5-sulfonamide (CAS #415913-05-2) (48 mg, 0.23 mmol).The reaction mixture was stirred at reflux for 3.5 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound. ¹H NMR(400 MHz, methanol-d₄) δ ppm 9.02-8.93 (m, 2H), 8.46 (dd, J=7.5, 1.3 Hz,1H), 8.34 (dt, J=8.5, 1.1 Hz, 1H), 7.93 (dd, J=8.5, 7.4 Hz, 1H), 7.88(dd, J=2.4, 0.7 Hz, 1H), 7.63 (dd, J=8.7, 4.3 Hz, 1H), 7.46 (d, J=2.4Hz, 1H), 3.85 (q, J=7.0 Hz, 2H), 3.52 (p, J=9.3, 8.8 Hz, 1H), 2.40-2.27(m, 2H), 2.24-2.10 (m, 2H), 2.10-1.98 (m, 1H), 1.95-1.83 (m, 1H),1.41-1.35 (m, 2H), 1.01 (q, J=4.4 Hz, 2H), 0.80 (t, J=7.0 Hz, 3H). MS(ESI+) m/z 452 (M+H)⁺.

Example GI-1151-(5-cyclobutyl-2-ethoxypyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(5-cyclobutyl-2-ethoxy-3-pyridyl)cyclopropanecarboxylic acid (60 mg,0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(CAS #25952-53-8) (53 mg, 0.276 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (34 mg, 0.276 mmol) in anhydrous dichloromethane (2 mL) wasadded to 2-methylquinoline-5-sulfonamide (51 mg, 0.23 mmol). Thereaction mixture was stirred at reflux for 3.5 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound. ¹H NMR(400 MHz, methanol-d₄) δ ppm 8.83 (dd, J=8.9, 0.9 Hz, 1H), 8.38 (dd,J=7.4, 1.2 Hz, 1H), 8.24 (dt, J=8.5, 1.1 Hz, 1H), 7.91-7.83 (m, 2H),7.52 (d, J=8.9 Hz, 1H), 7.46 (dd, J=2.4, 0.6 Hz, 1H), 3.85 (q, J=7.0 Hz,2H), 3.58-3.44 (m, 1H), 2.77 (s, 3H), 2.40-2.27 (m, 2H), 2.23-2.04 (m,3H), 1.95-1.83 (m, 1H), 1.41-1.30 (m, 2H), 1.04-0.97 (m, 2H), 0.80 (t,J=7.0 Hz, 3H). MS (ESI+) m/z 466 (M+H)⁺.

Example GI-1161-(2-ethoxy-5-ethylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-ethoxy-5-ethyl-3-pyridyl)cyclopropanecarboxylic acid (60 mg, 0.255mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (59 mg, 0.306 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (37 mg, 0.306 mmol) in anhydrous dichloromethane (2 mL) wasadded to quinoline-5-sulfonamide (CAS #415913-05-2) (53 mg, 0.255 mmol).The reaction mixture was stirred at reflux for 3.5 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound. ¹H NMR(400 MHz, methanol-d₄) δ ppm 9.02-8.93 (m, 2H), 8.47 (dd, J=7.5, 1.2 Hz,1H), 8.34 (dt, J=8.5, 1.1 Hz, 1H), 7.93 (dd, J=8.5, 7.4 Hz, 1H),7.89-7.84 (m, 1H), 7.63 (dd, J=8.8, 4.3 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H),3.85 (q, J=7.0 Hz, 2H), 2.59 (q, J=7.6 Hz, 2H), 1.41-1.32 (m, 2H), 1.23(t, J=7.6 Hz, 3H), 1.04-0.97 (m, 2H), 0.81 (t, J=7.1 Hz, 3H). MS (ESI+)m/z 426 (M+H)⁺.

Example GI-1171-(2-ethoxy-5-ethylpyridin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide

Into a vial, a solution of1-(2-ethoxy-5-ethyl-3-pyridyl)cyclopropanecarboxylic acid (60 mg, 0.255mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (59 mg, 0.306 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (37 mg, 0.306 mmol) in anhydrous dichloromethane (2 mL) wasadded to 2-methylquinoline-5-sulfonamide (57 mg, 0.255 mmol). Thereaction mixture was stirred at reflux for 3.5 hours. The reactionmixture was quenched with saturated aqueous NH₄Cl solution, and theaqueous layer was extracted with dichloromethane. The organic layerswere combined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 μm OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound. ¹H NMR(400 MHz, methanol-d₄) δ ppm 8.83 (dd, J=8.9, 0.9 Hz, 1H), 8.38 (dd,J=7.5, 1.2 Hz, 1H), 8.24 (dt, J=8.5, 1.1 Hz, 1H), 7.91-7.83 (m, 2H),7.52 (d, J=8.9 Hz, 1H), 7.42 (d, J=2.3 Hz, 1H), 3.85 (q, J=7.0 Hz, 2H),2.77 (s, 3H), 2.59 (q, J=7.6 Hz, 2H), 1.40-1.33 (m, 2H), 1.23 (t, J=7.6Hz, 3H), 1.04-0.96 (m, 2H), 0.81 (t, J=7.0 Hz, 3H). MS (ESI+) m/z 440(M+H)⁺.

Example GI-1181-{5-cyclobutyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-[5-cyclobutyl-2-[4-(methoxymethyl)-1-piperidyl]-3-pyridyl]cyclopropanecarboxylicacid (29 mg, 0.084 mmol) in anhydrous dichloromethane (2 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (32 mg, 0.168 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (10 mg, 0.084 mmol) were added, followed by1H-indole-4-sulfonamide (15 mg, 0.076 mmol). The reaction mixture wasstirred at reflux overnight. The reaction mixture was dried under N₂flow and the crude material was purified by reverse-phase HPLC WatersXBridge™ C18 5 m OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%formic acid/acetonitrile+0.1% formic acid to give the title compound. ¹HNMR (400 MHz, chloroform-d) δ ppm 8.96 (dd, J=4.2, 1.6 Hz, 1H), 8.86(dt, J=8.8, 1.2 Hz, 1H), 8.50 (dd, J=7.5, 1.2 Hz, 1H), 8.37 (dt, J=8.5,1.1 Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 8.11 (s, 1H), 7.83 (dd, J=8.5, 7.5Hz, 1H), 7.41 (dd, J=8.8, 4.2 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 3.48 (dq,J=10.7, 7.4, 5.2 Hz, 3H), 3.36 (s, 3H), 3.25 (d, J=6.0 Hz, 2H), 2.94(td, J=12.5, 2.3 Hz, 2H), 2.34 (dddd, J=9.9, 7.1, 5.1, 2.9 Hz, 2H),2.13-2.01 (m, 3H), 1.95-1.83 (m, 1H), 1.81-1.71 (m, 3H), 1.56 (q, J=4.3Hz, 2H), 1.53-1.38 (m, 2H), 1.12 (q, J=4.3 Hz, 2H). MS (ESI+) m/z 523(M+H)⁺.

Example GI-1191-{5-[1-(methoxymethyl)cyclopropyl]-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (28 mg, 0.149 mmol), 4-dimethylaminopyridine (CAS#1122-58-3) (18 mg, 0.149 mmol) and1-[2-isopropoxy-5-[1-(methoxymethyl)cyclopropyl]-3-pyridyl]cyclopropanecarboxylicacid (38 mg, 0.124 mmol) in anhydrous dichloromethane (2 mL), was addednaphthalene-1-sulfonamide (CAS #606-25-7) (26 mg, 0.124 mmol) and thereaction mixture was stirred at reflux for 2 hours. The reaction mixturewas quenched with saturated aqueous NH₄Cl solution. The aqueous layerwas extracted with dichloromethane, and the organic layers werecombined, dried over MgSO₄, filtered and concentrated. The crudematerial was purified by reverse-phase HPLC Waters XBridge™ C18 5 m OBDcolumn, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1%diethylamine/acetonitrile+0.1% diethylamine to give the title compound.¹H NMR (400 MHz, methanol-d₄) δ ppm 8.80-8.73 (m, 1H), 8.21 (dd, J=7.3,1.3 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.97-7.92 (m, 1H), 7.89 (d, J=2.4Hz, 1H), 7.62-7.53 (m, 2H), 7.51 (dd, J=8.2, 7.3 Hz, 1H), 7.45 (d, J=2.4Hz, 1H), 4.97 (p, J=6.1 Hz, 2H), 3.45 (s, 2H), 3.31 (s, 3H), 1.51 (q,J=3.9 Hz, 2H), 1.00 (d, J=6.1 Hz, 6H), 0.88-0.81 (m, 6H). MS (ESI+) m/z495 (M+H)⁺.

Example GI-1201-{5-ethyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(1H-indole-4-sulfonyl)cyclopropane-1-carboxamide

Into a vial, to a solution of1-[5-ethyl-2-[4-(methoxymethyl)-1-piperidyl]-3-pyridyl]cyclopropanecarboxylicacid (50 mg, 0.157 mmol) in anhydrous dichloromethane (3 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (60 mg, 0.314 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (19 mg, 0.157 mmol) were added, followed by1H-indole-4-sulfonamide (28 mg, 0.141 mmol). The reaction mixture wasstirred at reflux for 2 hours. The reaction mixture was quenched withsaturated aqueous NH₄Cl solution, and the organic layer was separated ona phase separator and concentrated. The crude material was purified byreverse-phase HPLC Waters XBridge™ C18 5 m OBD column, 30×100 mm, flowrate 50 mL/minute, H₂O+0.1% formic acid/acetonitrile+0.1% formic acid togive the title compound. ¹H NMR (400 MHz, chloroform-d) δ ppm 8.76 (s,1H), 8.14 (d, J=2.3 Hz, 1H), 7.91 (dd, J=7.7, 0.9 Hz, 1H), 7.66-7.58 (m,1H), 7.36 (d, J=2.4 Hz, 1H), 7.32 (t, J=2.9 Hz, 1H), 7.27 (t, J=7.9 Hz,1H), 6.80 (ddd, J=3.1, 2.0, 0.9 Hz, 1H), 3.34 (s, 5H), 3.17 (d, J=6.5Hz, 2H), 2.73 (td, J=12.3, 2.4 Hz, 2H), 2.58 (q, J=7.6 Hz, 2H), 1.65(tq, J=11.2, 4.2, 3.7 Hz, 1H), 1.57 (dt, J=7.1, 3.4 Hz, 4H), 1.27-1.15(m, 5H), 1.12 (q, J=4.2 Hz, 2H). MS (ESI+) m/z 497 (M+H)⁺.

Example GI-1211-{5-cyclobutyl-2-[4-(methoxymethyl)piperidin-1-yl]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide

To a solution of1-[5-cyclobutyl-2-[4-(methoxymethyl)-1-piperidyl]-3-pyridyl]cyclopropanecarboxylicacid (118 mg, 0.179 mmol) in anhydrous dichloromethane (3 mL),N,N-diisopropylethylamine (125 μL, 0.716 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS#25952-53-8) (73 mg, 0.358 mmol) and 4-dimethylaminopyridine (CAS#1122-58-3) (23 mg, 0.179 mmol) were added, followed byquinoline-5-sulfonamide (CAS #415913-05-2) (36 mg, 0.16 mmol). Thereaction mixture was stirred at ambient temperature overnight. Thereaction mixture was quenched with saturated aqueous NH₄Cl solution, andthe organic layer was separated on phase separator and concentrated. Thecrude material was purified by reverse-phase HPLC Waters XBridge™ C18 5m OBD column, 30×100 mm, flow rate 50 mL/minute, H₂O+0.1% formicacid/acetonitrile+0.1% formic acid to give the title compound. ¹H NMR(400 MHz, chloroform-d) δ ppm 8.96 (dd, J=4.2, 1.6 Hz, 1H), 8.86 (dt,J=8.8, 1.2 Hz, 1H), 8.50 (dd, J=7.5, 1.2 Hz, 1H), 8.37 (dt, J=8.5, 1.1Hz, 1H), 8.21 (d, J=2.3 Hz, 1H), 8.11 (s, 1H), 7.83 (dd, J=8.5, 7.5 Hz,1H), 7.41 (dd, J=8.8, 4.2 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 3.48 (dq,J=10.7, 7.4, 5.2 Hz, 3H), 3.36 (s, 3H), 3.25 (d, J=6.0 Hz, 2H), 2.94(td, J=12.5, 2.3 Hz, 2H), 2.34 (dddd, J=9.9, 7.1, 5.1, 2.9 Hz, 2H),2.13-2.01 (m, 3H), 1.95-1.83 (m, 1H), 1.81-1.71 (m, 3H), 1.56 (q, J=4.3Hz, 2H), 1.53-1.38 (m, 2H), 1.12 (q, J=4.3 Hz, 2H). MS (ESI+) m/z 535(M+H)⁺.

TABLE 4 Name NMR MS Example 1-(2,4- ¹H NMR (400 MHz, methanol-d₄) δ ppm8.73-8.64 MS GII-1 dimethoxypyrimidin- (m, 1H), 8.18 (dd, J = 7.3, 1.3Hz, 1H), 8.03-7.94 (m, (ESI+) 5-yl)-N-(naphthalene- 2H), 7.94-7.86 (m,1H), 7.57-7.52 (m, 2H), 7.50 m/z 414 1-sulfonyl)cyclopropane- (dd, J =8.2, 7.3 Hz, 1H), 3.94 (s, 3H), 3.68 (s, 3H), (M + H)⁺. 1-carboxamide1.38 (q, J = 3.8 Hz, 2H), 0.81 (q, J = 3.9 Hz, 2H). ExampleN-(naphthalene-1- ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.78-8.69 MS GII-2sulfonyl)-1-{2- (m, 1H), 8.17 (dd, J = 7.3, 1.3 Hz, 1H), 7.96 (dt, J =(ESI+) [(propan-2- 8.3, 1.1 Hz, 1H), 7.89 (ddd, J = 9.0, 4.7, 1.8 Hz,2H), m/z 411 yl)oxy]pyridin-3- 7.57-7.50 (m, 2H), 7.49-7.41 (m, 2H),6.77 (dd, J = (M + H)⁺. yl}cyclopropane-1- 7.3, 5.1 Hz, 1H), 4.97 (hept,J = 6.1 Hz, 1H), 1.49 (q, J = carboxamide 3.8 Hz, 2H), 0.96 (d, J = 6.2Hz, 6H), 0.82 (q, J = 3.9 Hz, 2H). Example 1-{2-[(propan-2- ¹H NMR (400MHz, methanol-d₄) δ ppm 9.16 (ddd, J = MS GII-3 yl)oxy]pyridin-3-yl}-8.8, 1.7, 0.9 Hz, 1H), 8.88 (dd, J = 4.3, 1.7 Hz, 1H), (ESI+)N-(quinoline-5- 8.25 (dd, J = 7.3, 1.2 Hz, 1H), 8.11 (dt, J = 8.5, 1.1Hz, m/z 412 sulfonyl)cyclopropane- 1H), 7.87 (dd, J = 5.1, 1.9 Hz, 1H),7.77 (dd, J = 8.5, (M + H)⁺. 1-carboxamide 7.3 Hz, 1H), 7.57 (dd, J =8.7, 4.3 Hz, 1H), 7.45 (dd, J = 12, 1.9 Hz, 1H), 6.78 (dd, J = 7.2, 5.1Hz, 1H), 4.94 (h, J = 6.1 Hz, 1H), 1.46 (q, J = 3.9 Hz, 2H), 0.90 (d, J= 6.2 Hz, 6H), 0.82 (q, J = 3.9 Hz, 2H). Example 1-{2-[(propan-2- ¹H NMR(400 MHz, methanol-d₄) δ ppm 7.91 (dd, J = MS GII-4yl)oxy]pyridin-3-yl}- 5.1, 1.9 Hz, 1H), 7.51 (dd, J = 7.2, 2.0 Hz, 1H),7.20 (ESI+) N-(1,2,3,4- (dd, J = 7.8, 1.3 Hz, 1H), 6.89 (t, J = 7.9 Hz,1H), 6.81 m/z 416 tetrahydroquinoline-5- (dd, J = 7.2, 5.1 Hz, 1H), 6.57(dd, J = 8.0, 1.2 Hz, (M + H)⁺. sulfonyl)cyclopropane- 1H), 5.19 (hept,J = 6.2 Hz, 1H), 3.26-3.19 (m, 2H), 1-carboxamide 3.08 (t, J = 6.4 Hz,2H), 1.90-1.79 (m, 2H), 1.52 (q, J = 3.8 Hz, 2H), 1.28 (d, J = 62 Hz,6H), 0.87 (q, J = 3.9 Hz, 2H). Example 1-[5-chloro-2- ¹H NMR (400 MHz,chloroform-d) δ ppm 8.52-8.44 MS GII-5 (trifluoromethyl)pyridin- (m,2H), 8.29-8.22 (m, 1H), 8.18 (d, J = 8.2 Hz, 1H), (ESI+) 3-yl]-N- 8.12(s, 1H), 8.04-7.96 (m, 1H), 7.75 (d, J = 2.2 Hz, m/z 455 (naphthalene-1-1H), 7.72-7.59 (m, 3H), 1.56-1.52 (m, 2H), 1.13 (d, (M + H)⁺.sulfonyl)cyclopropane- J = 3.6 Hz, 2H). 1-carboxamide Example1-(5-chloro-2- ¹H NMR (400 MHz, chloroform-d) δ ppm 9.05 (dd, J = MSGII-6 methoxypyridin-4-yl)- 4.2, 1.6 Hz, 1H), 8.82 (ddd, J = 8.7, 1.6,0.9 Hz, 1H), (ESI+) N-(quinoline-5- 8.52 (dd, J = 7.5, 1.3 Hz, 1H), 8.43(dt, J = 8.5, 1.1 Hz, m/z 418 sulfonyl)cyclopropane- 1H), 8.12-8.07 (m,1H), 7.86 (dd, J = 8.5, 7.5 Hz, (M + H)⁺. 1-carboxamide 1H), 7.58 (dd, J= 8.8, 4.2 Hz, 1H), 6.70 (d, J = 0.5 Hz, 1H), 3.91 (s, 3H), 1.64-1.60(m, 2H), 1.08 (q, J = 4.4 Hz, 2H). Example 1-(5-chloro-2- ¹H NMR (400MHz, chloroform-d) δ ppm 8.00 (s, 1H), MS GII-7 methoxypyridin-4-yl)-7.48 (dd, J = 7.9, 1.6 Hz, 1H), 6.91 (dd, J = 7.3, 1.6 Hz, (ESI+)N-(1,2,3,4- 1H), 6.65 (s, 1H), 6.42 (t, J = 7.6 Hz, 1H), 3.86 (s, 3H),m/z 422 tetrahydroquinoline-5- 3.27-3.20 (m, 3H), 2.71 (t, J = 6.3 Hz,2H), 1.88- (M + H)⁺. sulfonyl)cyclopropane-1- 1.79 (m, 2H), 1.55 (q, J =3.8 Hz, 2H), 0.93 (q, J = 3.8 carboxamide Hz, 2H). Example1-[5-methyl-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.11 (ddd, J = MSGII-8 (morpholin-4- 8.8, 1.7, 0.9 Hz, 1H), 8.91 (dd, J = 4.3, 1.7 Hz,1H), (ESI+) yl)pyridin-4-yl]-N- 8.32 (dd, J = 7.4, 1.2 Hz, 1H), 8.18(dt, J = 8.5, 1.1 Hz, m/z 453 (quinoline-5- 1H), 8.12 (s, 1H), 7.83 (dd,J = 8.5, 7.3 Hz, 1H), 7.64- (M + H)⁺. sulfonyl)cyclopropane-1- 7.56 (m,2H), 6.97 (s, 1H), 3.82 (dt, J = 8.2, 4.9 Hz, carboxamide 4H), 3.57-3.49(m, 4H), 2.67 (s, 3H), 1.48 (q, J = 3.6 Hz, 2H), 0.98 (q, J = 3.9 Hz,2H). Example 1-[5-methyl-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.13(dt, J = MS GII-9 (pyrrolidin-1- 8.6, 1.4 Hz, 1H), 8.90 (dd, J = 4.3,1.7 Hz, 1H), 8.31 (ESI+) yl)pyridin-4-yl]-N- (dd, J = 7.3, 1.2 Hz, 1H),8.15 (dt, J = 8.5, 1.1 Hz, 1H), m/z 437 (quinoline-5- 7.81 (dd, J = 8.5,7.3 Hz, 1H), 7.58 (dd, J = 8.7, 4.3 Hz, (M + H)⁺. sulfonyl)cyclopropane-1H), 7.47 (s, 1H), 6.67 (s, 1H), 3.57-3.44 (m, 4H), 1-carboxamide2.19-2.05 (m, 4H), 1.87 (d, J = 0.9 Hz, 3H), 1.47 (d, J = 3.0 Hz, 2H),0.94 (q, J = 3.8 Hz, 2H). Example 1-[2-methoxy-6- ¹H NMR (400 MHz,mehanol-d₄) δ ppm 9.09 (ddd, J = MS GII-10 (trifluoromethyl)pyridin-8.7, 1.7, 0.9 Hz, 1H), 8.89 (dd, J = 4.3, 1.7 Hz, 1H), (ESI+)3-yl]-N-(quinoline-5- 8.29 (dd, J = 7.3, 1.2 Hz, 1H), 8.14 (dt, J = 8.5,1.1 Hz, m/z 452 sulfonyl)cyclopropane- 1H), 7.80 (dd, J = 8.5, 7.3 Hz,1H), 7.62 (dd, J = 7.5, (M + H)⁺. 1-carboxamide 0.8 Hz, 1H), 7.55 (dd, J= 8.8, 4.3 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 3.58 (s, 3H), 1.41 (q, J =4.0 Hz, 2H), 0.85 (q, J = 4.0 Hz, 2H). Example 1-[2-(dimethylamino)- ¹HNMR (400 MHz, methanol-d₄) δ ppm 9.12 (ddd, J = MS GII-115-methylpyridin-4-yl]- 8.7, 1.7, 0.9 Hz, 1H), 8.86 (dd, J = 4.3, 1.7 Hz,1H), (ESI+) N-(quinoline-5- 8.26 (dd, J = 7.3, 1.3 Hz, 1H), 8.11 (dt, J= 8.5, 1.1 Hz, m/z 411 sulfonyl)cyclopropane- 1H), 7.77 (dd, J = 8.5,7.3 Hz, 1H), 7.61 (t, J = 0.7 Hz, (M + H)⁺. 1-carboxamide 1H), 7.53 (dd,J = 8.8, 4.3 Hz, 1H), 6.47 (s, 1H), 2.99 (s, 6H), 1.78 (d, J = 0.8 Hz,3H), 1.41 (q, J = 3.6 Hz, 2H), 1.25 (t, J = 7.3 Hz, 7H), 0.84 (q, J =3.6 Hz, 2H). Example 1-[2-methoxy-6- ¹H NMR (400 MHz, methanol-d₄) δ ppm7.79 (d, J = MS GII-12 (trifluoromethyl)pyridin- 7.5 Hz, 1H), 7.35 (d, J= 7.5 Hz, 1H), 7.26 (dd, J = 7.8, (ESI+) 3-yl]-N-(1,2,3,4- 1.2 Hz, 1H),7.04 (t, J = 8.0 Hz, 1H), 6.75 (dd, J = 8.1, m/z 456tetrahydroquinoline-5- 1.2 Hz, 1H), 3.92 (s, 3H), 3.30-3.24 (m, 2H),2.92 (t, (M + H)⁺. sulfonyl)cyclopropane- J = 6.4 Hz, 2H), 1.92-1.82 (m,2H), 1.57-1.51 (m, 1-carboxamide 2H), 1.15 (q, J = 4.5 Hz, 2H). Example1-(2-methoxy-5- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.04-8.95 MS GII-13methylpyridin-4-yl)- (m, 2H), 8.44 (dd, J = 7.4, 1.2 Hz, 1H), 8.32 (dt,J = (ESI+) N-(quinoline-5- 8.5, 1.1 Hz, 1H), 7.91 (dd, J = 8.5, 7.4 Hz,1H), 7.81- m/z 398 sulfonyl)cyclopropane- 7.76 (m, 1H), 7.64 (dd, J =8.8, 4.3 Hz, 1H), 6.72 (s, (M + H)⁺. 1-carboxamide 1H), 3.90 (s, 3H),1.77 (d, J = 0.9 Hz, 3H), 1.46-1.39 (m, 2H), 1.10-1.02 (m, 2H). Example1-[2-cyclobutyl-6- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.14 (ddd, J = MSGII-14 (trifluoromethyl)pyridin- 8.7, 1.6, 0.9 Hz, 1H), 8.90 (dd, J =4.3, 1.7 Hz, 1H), (ESI+) 3-yl]-N-(quinoline-5- 8.27 (dd, J = 7.3, 1.2Hz, 1H), 8.13 (dt, J = 8.5, 1.1 Hz, m/z 476 sulfonyl)cyclopropane- 1H),7.78 (dd, J = 8.5, 7.3 Hz, 1H), 7.63 (dd, J = 7.9, (M + H)⁺.1-carboxamide 0.8 Hz, 1H), 7.58 (dd, J = 8.7, 4.3 Hz, 1H), 7.41 (d, J =7.9 Hz, 1H), 3.78-3.65 (m, 1H), 2.26-2.12 (m, 2H), 1.82-1.60 (m, 4H),1.58 (q, J = 4.5, 3.1 Hz, 2H), 0.88 (d, J = 4.3 Hz, 2H). Example1-(2-cyclopropyl-5- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.08-9.02 MSGII-15 methoxypyridin-3-yl)- (m, 1H), 8.97 (dd, J = 4.3, 1.6 Hz, 1H),8.42 (dd, J = (ESI+) N-(quinoline-5- 7.4, 1.2 Hz, 1H), 8.29 (dt, J =8.5, 1.1 Hz, 1H), 7.98 (d, m/z 424 sulfonyl)cyclopropane- J = 2.8 Hz,1H), 7.93-7.87 (m, 1H), 7.62 (dd, J = 8.8, (M + H)⁺. 1-carboxamide 4.3Hz, 1H), 7.44 (d, J = 2.8 Hz, 1H), 3.90 (s, 3H), 1.88 (tt, J = 8.3, 5.1Hz, 1H), 1.57 (q, J = 4.1 Hz, 2H), 1.16 (q, J = 4.0 Hz, 2H), 0.76 (dt, J= 6.2, 3.1 Hz, 2H), 0.64 (dt, J = 8.3, 3.2 Hz, 2H). Example1-{2-ethyl-5-[(propan- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.21-9.11 MSGII-16 2-yl)oxy]pyridin-3- (m, 1H), 8.90 (dd, J = 4.3, 1.7 Hz, 1H),8.31-8.23 (m, (ESI+) yl}-N-(quinoline-5- 1H), 8.13 (dt, J = 8.5, 1.1 Hz,1H), 7.88 (d, J = 2.8 Hz, m/z 440 sulfonyl)cyclopropane- 1H), 7.83-7.75(m, 1H), 7.61-7.53 (m, 1H), 7.13 (d, (M + H)⁺. 1-carboxamide J = 2.8 Hz,1H), 4.65-4.51 (m, J = 6.1 Hz, 1H), 2.47 (q, J = 7.6 Hz, 2H), 1.53 (p, J= 3.6 Hz, 2H), 1.34- 1.23 (m, 6H), 0.89 (t, J = 7.5 Hz, 5H). Example1-(2-ethyl-5- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.13 (ddd, J = MSGII-17 methoxypyridin-3-yl)- 8.7, 1.7, 0.9 Hz, 1H), 8.89 (dd, J = 4.3,1.7 Hz, 1H), (ESI+) N-(quinoline-5- 8.25 (dd, J = 7.3, 1.2 Hz, 1H), 8.12(dt, J = 8.5, 1.1 Hz, m/z 412 sulfonyl)cyclopropane- 1H), 7.92 (d, J =2.9 Hz, 1H), 7.78 (dd, J = 8.5, 7.3 Hz, (M + H)⁺. 1-carboxamide 1H),7.57 (dd, J = 8.7, 4.3 Hz, 1H), 7.15 (d, J = 2.9 Hz, 1H), 3.81 (s, 3H),2.46 (q, J = 7.5 Hz, 2H), 1.56-1.49 (m, 2H), 0.95-0.90 (m, 2H), 0.88 (t,J = 7.6 Hz, 3H). Example 1-[6-(dimethylamino)- ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.17 (ddd, J = MS GII-18 2-methoxypyridin-3- 8.7,1.7, 0.9 Hz, 1H), 8.87 (dd, J = 4.3, 1.6 Hz, 1H), (ESI+)yl]-N-(quinoline-5- 8.27 (dd, J = 7.4, 1.2 Hz, 1H), 8.11 (dt, J = 8.5,1.1 Hz, m/z 427 sulfonyl)cyclopropane- 1H), 7.77 (dd, J = 8.5, 7.3 Hz,1H), 7.56 (dd, J = 8.7, (M + H)⁺. 1-carboxamide 4.3 Hz, 1H), 7.20 (d, J= 8.1 Hz, 1H), 5.96 (d, J = 8.1 Hz, 1H), 3.53 (s, 3H), 2.98 (s, 6H),1.32 (q, J = 3.7 Hz, 2H), 0.74 (q, J = 3.7 Hz, 2H). Example1-(6-methoxy-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.76-8.69 MS GII-19methylpyridin-3-yl)- (m, 1H), 8.17 (dd, J = 7.3, 1.3 Hz, 1H), 8.76-8.69(dt, (ESI+) N-(naphthalene-1- J = 8.3, 1.1 Hz, 1H), 7.89-7.83 (m, 2H),7.56-7.48 m/z 387 sulfonyl)cyclopropane- (m, 2H), 7.45 (dd, J = 8.2, 7.3Hz, 1H), 7.40 (d, J = 8.3 1-carboxamide Hz, 1H), 6.46 (d, J = 8.4 Hz,1H), 3.80 (s, 3H), 2.16 (s, 3H), 1.49 (q, J = 3.4 Hz, 2H), 0.81 (q, J =3.4 Hz, 2H). (M + H)⁺. Example 1-(4-ethylpyridin-3- ¹H NMR (400 MHz,methanol-d₄) δ ppm 8.74-8.66 MS GII-20 yl)-N-(naphthalene-1- (m, 1H),8.24-8.19 (m, 2H), 8.17 (dd, J = 7.3, 1.3 Hz, (ESI+)sulfonyl)cyclopropane- 1H7.94 (dt, J = 8.5, 1.2 Hz, 1H), 7.91-7.84 (m,1H), m/z 381 1-carboxamide 7.53 (ddd, J = 5.5, 4.6, 3.3 Hz, 2H), 7.45(dd, J = 8.2, (M + H)⁺. 7.3 Hz, 1H), 7.15-7.09 (m, 1H), 3.10 (s, 3H),2.45 (q, J = 7.5 Hz, 2H), 1.55 (d, J = 3.6 Hz, 2H), 0.93 (t, J = 7.5 Hz,3H), 0.88 (q, J = 3.3 Hz, 2H). Example 1-(4-ethylpyridin-3- ¹H NMR (400MHz, methanol-d₄) δ ppm 8.30 (s, 1H), MS GII-21 yl)-N-(1,2,3,4- 8.26 (d,J = 5.2 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 7.20 (ESI+)tetrahydroquinoline-5- (dd, J = 7.8, 1.3 Hz, 1H), 6.90 (t, J = 7.9 Hz,1H), 6.58 m/z 386 sulfonyl)cyclopropane- (dd, J = 8.0, 1.2 Hz, 1H),3.26-3.19 (m, 2H), 3.05 (t, J = (M + H)⁺. 1-carboxamide 6.4 Hz, 2H),2.78 (q, J = 7.5 Hz, 2H), 1.89-1.78 (m, 2H), 1.60 (d, J = 3.6 Hz, 2H),1.21 (t, J = 7.6 Hz, 3H), 0.96 (q, J = 3.3 Hz, 2H). Example1-(6-methoxy-4- ¹H NMR (400 MHz, methanol-d₄) δ ppm 8.74-8.69 MS GII-22methylpyridin-3-yl)- (m, 1H), 8.18 (dd, J = 7.3, 1.3 Hz, 1H), 7.97-7.92(m, (ESI+) N-(naphthalene-1- 1H), 7.91-7.86 (m, 1H), 7.80 (s, 1H),7.55-7.50 (m, m/z 397 sulfonyl)cyclopropane- 2H), 7.47 (dd, J = 8.2, 7.3Hz, 1H), 6.50-6.45 (m, (M + H)⁺. 1-carboxamide 1H), 3.81 (s, 3H), 2.00(d, J = 0.8 Hz, 3H), 1.49 (d, J = 3.4 Hz, 2H), 0.83 (q, J = 3.2 Hz, 2H).Example 1-(6-methoxy-4- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.15 (ddd, J= MS GII-23 methylpyridin-3-yl)- 8.7, 1.7, 0.9 Hz, 1H), 8.89 (dd, J =4.3, 1.7 Hz, 1H), (ESI+) N-(quinoline-5- 8.26 (dd, J = 7.3, 1.3 Hz, 1H),8.13 (dt, J = 8.5, 1.1 Hz, m/z 398 sulfonyl)cyclopropane- 1H), 7.83-7.75(m, 2H), 7.58 (dd, J = 8.8, 4.3 Hz, (M + H)⁺. 1-carboxamide 1H),6.52-6.47 (m, 1H), 3.84 (s, 3H), 2.00 (d, J = 0.8 Hz, 3H), 1.47 (d, J =3.5 Hz, 2H), 0.86 (q, J = 3.2 Hz, 2H). Example 1-{6-methoxy-4- ¹H NMR(400 MHz, methanol-d₄) δ ppm 7.74 (s, 1H), MS GII-24 [(propan-2- 7.18(dd, J = 7.8, 1.2 Hz, 1H), 6.88 (t, J = 7.9 Hz, 1H), (ESI+)yl)oxy]pyridin-3-yl}- 6.56 (dd, J = 8.0, 1.2 Hz, 1H), 6.21 (s, 1H), 4.59(hept, m/z 446 N-(1,2,3,4- J = 6.0 Hz, 1H), 3.84 (s, 3H), 3.25-3.18 (m,2H), 3.14- (M + H)⁺. tetrahydroquinoline-5- 3.05 (m, 2H), 1.89-1.79 (m,2H), 1.48 (q, J = 3.7 sulfonyl)cyclopropane- Hz, 2H), 1.22 (t, J = 7.3Hz, 6H), 0.84 (q, J = 3.8 Hz, 1-carboxamide 2H). Example1-{5-cyclobutyl-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.74 (dd, J = MSGII-25 [(propan-2- 2.4, 0.7 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.20 (dd,J = (ESI+) yl)oxy]pyridin-3-yl}- 7.8, 1.2 Hz, 1H), 6.89 (t, J = 7.9 Hz,1H), 6.56 (dd, J = m/z 470 N-(1,2,3,4- 8.1, 1.2 Hz, 1H), 5.13 (hept, J =6.1 Hz, 1H), 3.47 (p, J = (M + H)⁺. tetrahydroquinoline-5- 8.5 Hz, 1H),3.40-3.33 (m, 1H), 3.24-3.19 (m, sulfonyl)cyclopropane- 2H), 3.05 (t, J= 6.4 Hz, 2H), 2.32-2.25 (m, 2H), 2.18- 1-carboxamide 1.98 (m, 3H),1.91-1.79 (m, 3H), 1.50 (q, J = 3.9 Hz, 2H), 1.27-1.24 (m, 6H), 0.87 (q,J = 3.9 Hz, 2H). Example 1-{2-cyclobutyl-5- ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.96 (s, 1H), MS GII-26 [(propan-2- 7.20 (dd, J =7.7, 1.2 Hz, 1H), 7.14 (s, 1H), 6.88 (t, J = (ESI+)yl)oxy]pyridin-4-yl}- 7.9 Hz, 1H), 6.56 (dd, J = 8.0, 1.2 Hz, 1H), 4.58(hept, m/z 470 N-(1,2,3,4- J = 6.0 Hz, 1H), 3.59 (tt, J = 10.0, 8.2 Hz,1H), 3.23- (M + H)⁺. tetrahydroquinoline-5- 3.18 (m, 2H), 3.03 (t, J =6.4 Hz, 2H), 2.36-2.18 (m, sulfonyl)cyclopropane- 4H), 2.12-1.95 (m,1H), 1.92-1.77 (m, 3H), 1.50 (q, 1-carboxamide J = 3.9 Hz, 2H),1.29-1.24 (m, 6H), 0.90 (q, J = 4.0 Hz, 2H). Example 1-{5-cyclobutyl-3-¹H NMR (400 MHz, methanol-d₄) δ ppm 9.18 (ddd, J = MS GII-27 [(propan-2-8.8, 1.7, 0.9 Hz, 1H), 8.87 (dd, J = 4.3, 1.6 Hz, 1H), (ESI+)yl)oxy]pyridin-2-yl}- 8.24 (dd, J = 7.3, 1.2 Hz, 1H), 8.10 (dt, J = 8.5,1.1 Hz, m/z 466 N-(quinoline-5- 1H), 7.76 (dd, J = 8.5, 7.3 Hz, 1H),7.72 (d, J = 1.7 Hz, (M + H)⁺. sulfonyl)cyclopropane- 1H), 7.57 (dd, J =8.7, 4.3 Hz, 1H), 7.04 (d, J = 1.8 Hz, 1-carboxamide 1H), 4.39 (hept, J= 6.0 Hz, 1H), 3.58-3.45 (m, 1H), 2.39-2.26 (m, 2H), 2.19-1.98 (m, 3H),1.92-1.83 (m, 1H), 1.48 (q, J = 3.9 Hz, 2H), 1.0-0.92 (m, 8H). Example1-[5-cyclobutyl-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.18 (ddd, J = MSGII-28 (morpholin-4- 8.7, 1.7, 0.9 Hz, 1H), 8.88 (dd, J = 4.3, 1.7 Hz,1H), (ESI+) yl)pyridin-3-yl]-N- 8.28 (dd, J = 7.3, 1.2 Hz, 1H), 8.11(dt, J = 8.5, 1.1 Hz, m/z 493 (quinoline-5- 1H), 7.85 (dd, J = 2.4, 0.7Hz, 1H), 7.78 (dd, J = 8.5, (M + H)⁺. sulfonyl)cyclopropane- 7.3 Hz,1H), 7.57 (dd, J = 8.7, 4.3 Hz, 1H), 7.49 (dd, J = 1-carboxamide 2.4,0.6 Hz, 1H), 3.46 (t, J = 4.7 Hz, 5H), 2.96-2.91 (m, 4H), 2.35-2.25 (m,2H), 2.16-1.98 (m, 3H), 1.92- 1.80 (m, 1H), 1.49 (q, J = 3.7 Hz, 2H),0.99 (q, J = 3.8 Hz, 2H). Example 1-[5-cyclopropyl-2- ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.65 (d, J = MS GII-29 (pyrrolidin-1- 2.4 Hz, 1H),7.25-7.18 (m, 2H), 6.89 (t, J = 7.9 Hz, (ESI+) yl)pyridin-3-yl]-N- 1H),6.56 (dd, J = 8.0, 1.3 Hz, 1H), 3.56-3.40 (m, m/z 467 (1,2,3,4- 4H),3.22 (t, J = 5.6 Hz, 2H), 3.11 (t, J = 6.5 Hz, 2H), (M + H)⁺.tetrahydroquinoline-5- 1.90-1.69 (m, 7H), 1.55 (q, J = 3.6 Hz, 2H), 0.95(q, J = sulfonyl)cyclopropane- 3.6 Hz, 2H), 0.90-0.79 (m, 2H), 0.60-0.52(m, 1-carboxamide 2H). Example 1-[5-ethyl-2- ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.19-9.12 MS GII-30 (pyrrolidin-1- (m, 1H), 8.91 (dd,J = 4.3, 1.6 Hz, 1H), 8.31 (dd, J = (ESI+) yl)pyridin-3-yl]-N- 7.3, 1.2Hz, 1H), 8.15 (dt, J = 8.5, 1.1 Hz, 1H), 7.84- m/z 451 (quinoline-5-7.79 (m, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = (M + H)⁺.sulfonyl)cyclopropane- 8.7, 4.3 Hz, 1H), 7.44 (dd, J = 2.2, 1.0 Hz, 1H),3.47- 1-carboxamide 3.40 (m, 4H), 2.55 (q, J = 7.6 Hz, 2H), 1.65-1.57(m, 6H), 1.20 (t, J = 7.6 Hz, 3H), 1.17-1.12 (m, 2H). Example1-[5-ethyl-2- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.91 (d, J = 8.8 MS GII-31(pyrrolidin-1- Hz, 1H), 8.06-7.91 (m, 2H), 7.70 (t, J = 7.9 Hz, 1H),(ESI+) yl)pyridin-3-yl]-N-(2- 7.64-7.57 (m, 2H), 7.46 (d, J = 8.8 Hz,1H), 3.30- m/z 465 methylquinoline-5- 3.15 (m, 4H), 2.67 (s, 3H),2.55-2.45 (m, 2H), 1.55- (M + H)⁺. sulfonyl)cyclopropane- 1.32 (m, 6H),1.13 (t, J = 7.5 Hz, 3H), 1.09-0.98 (m, 1-carboxamide 2H). Example1-[5-ethyl-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.04 (d, J = MS GII-32(morpholin-4- 8.8 Hz, 1H), 8.22-8.15 (m, 1H), 8.04 (d, J = 8.4 Hz,(ESI+) yl)pyridin-3-yl]-N-(2- 1H), 7.86 (d, J = 2.5 Hz, 1H), 7.77-7.68(m, 1H), 7.49- m/z 481 methylquinoline-5- 7.43 (m, 2H), 3.50-3.43 (m,4H), 2.98-2.88 (m, (M + H)⁺. sulfonyl)cyclopropane- 4H), 2.74 (s, 3H),2.54 (q, J = 7.6 Hz, 2H), 1.50 (q, J = 1-carboxamide 3.7 Hz, 2H), 1.18(t, J = 7.6 Hz, 3H), 1.00 (q, J = 3.8 Hz, 2H). Example1-[2-(pyrrolidin-1- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.17 (ddd, J =MS GII-33 yl)pyridin-3-yl]-N- 8.7, 1.7, 0.9 Hz, 1H), 8.84 (dd, J = 4.3,1.7 Hz, 1H), (ESI+) (quinoline-5- 8.24 (dd, J = 7.3, 1.2 Hz, 1H), 8.08(dt, J = 8.5, 1.1 Hz, m/z 423 sulfonyl)cyclopropane- 1H), 7.79-7.69 (m,2H), 7.54 (dd, J = 8.7, 4.3 Hz, (M + H)⁺. 1-carboxamide 1H), 7.38 (dd, J= 7.3, 1.9 Hz, 1H), 6.52 (dd, J = 7.4, 5.0 Hz, 1H), 3.15 (d, J = 6.3 Hz,4H), 1.50 (q, J = 3.6 Hz, 2H), 1.41-1.31 (m, 4H), 0.90 (q, J = 3.2 Hz,2H). Example N-(2-methylquinoline- ¹H NMR (400 MHz, methanol-d₄) δ ppm9.06 (d, J = MS GII-34 5-sulfonyl)-1-[2- 8.8 Hz, 1H), 8.25 (d, J = 7.3Hz, 1H), 7.85-7.75 (m, (ESI+) (pyrrolidin-1- 3H), 7.68 (d, J = 6.3 Hz,1H), 7.54 (d, J = 8.9 Hz, 1H), m/z 437 yl)pyridin-3- 6.82 (t, J = 6.7Hz, 1H), 3.54-3.40 (d, J = 6.3 Hz, (M + H)⁺. yl]cyclopropane-1- 4H),2.76 (s, 3H), 1.69-1.57 (m, 6H), 1.20-1.13 (m, carboxamide 2H). Example1-[5-ethyl-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.65 (d, J = MS GII-35(pyrrolidin-1- 2.3 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.20 (dd, J = 7.7,(ESI+) yl)pyridin-3-yl]-N- 1.2 Hz, 1H), 6.89 (t, J = 7.9 Hz, 1H), 6.57(dd, J = 8.1, m/z 455 (1,2,3,4- 1.2 Hz, 1H), 3.57-3.44 (m, 4H),3.25-3.18 (m, 2H), (M + H)⁺. tetrahydroquinoline-5- 3.11 (t, J = 6.4 Hz,2H), 2.49 (q, J = 7.6 Hz, 2H), 1.85- sulfonyl)cyclopropane- 1.79 (m,4H), 1.68 (dd, J = 5.9, 1.9 Hz, 2H), 1.58 (q, 1-carboxamide J = 3.6 Hz,2H), 1.17 (t, J = 7.6 Hz, 3H), 1.02-0.99 (m, 2H). Example 1-[5-methyl-2-¹H NMR (400 MHz, methanol-d₄) δ ppm 9.07 (dd, J = MS GII-36(pyrrolidin-1- 8.8, 0.8 Hz, 1H), 8.21 (dd, J = 7.3, 1.2 Hz, 1H), 8.04(ESI+) yl)pyridin-3-yl]-N-(2- (dt, J = 8.5, 1.1 Hz, 1H), 7.73 (dd, J =8.5, 7.3 Hz, 1H), m/z 451 methylquinoline-5- 7.61 (dd, J = 2.3, 0.9 Hz,1H), 7.47 (d, J = 8.9 Hz, 1H), (M + H)⁺. sulfonyl)cyclopropane- 7.34 (d,J = 2.3 Hz, 1H), 3.22-3.14 (m, 4H), 2.74 (s, 1-carboxamide 3H), 2.14 (s,3H), 1.54 (q, J = 3.6 Hz, 2H), 1.47-1.39 (m, 4H), 0.95 (q, J = 3.5 Hz,2H). Example N-(1H-indole-4- ¹H NMR (400 MHz, methanol-d₄) δ ppm7.65-7.56 MS GII-37 sulfonyl)-1-[5-methyl- (m, 2H), 7.49 (dt, J = 8.1,0.9 Hz, 1H), 7.36 (d, J = 2.3 (ESI+) 2-(pyrrolidin-1- Hz, 1H), 7.31 (d,J = 3.1 Hz, 1H), 7.11 (t, J = 7.8 Hz, m/z 425 yl)pyridin-3- 1H), 6.86(dd, J = 3.1, 0.9 Hz, 1H), 3.27 (t, J = 5.4 Hz, (M + H)⁺.yl]cyclopropane-1- 4H), 2.13 (s, 3H), 1.60 (q, J = 3.6 Hz, 2H), 1.52(dq, J = carboxamide 9.1, 5.7, 4.5 Hz, 4H), 0.95 (q, J = 3.6 Hz, 2H).Example 1-[5-methyl-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.24-9.17 MSGII-38 (pyrrolidin-1- (m, 1H), 8.89 (dd, J = 4.3, 1.7 Hz, 1H), 8.29 (dd,J = (ESI+) yl)pyridin-3-yl]-N- 7.3, 1.3 Hz, 1H), 8.12 (d, J = 8.5 Hz,1H), 7.79 (dd, J = m/z 437 (quinoline-5- 8.5, 7.3 Hz, 1H), 7.63-7.55 (m,2H), 7.35 (d, J = 2.3 (M + H)⁺. sulfonyl)cyclopropane- Hz, 1H), 3.18 (d,J = 6.3 Hz, 4H), 2.14 (s, 3H), 1.55 (q, 1-carboxamide J = 3.6 Hz, 2H),1.48-1.37 (m, 4H), 0.96 (q, J = 3.5 Hz, 2H). Example 1-(3-cyclopropyl-5-¹H NMR (400 MHz, methanol-d₄) δ ppm 7.92 (dd, J = MS GII-39methylpyridin-2-yl)- 2.2, 0.9 Hz, 1H), 7.59 (dd, J = 7.4, 0.9 Hz, 1H),7.48 (ESI+) N-(1H-indole-4- (dt, J = 8.1, 1.0 Hz, 1H), 7.29 (d, J = 3.2Hz, 1H), 7.09 m/z 396 sulfonyl)cyclopropane- (t, J = 7.8 Hz, 1H), 6.95(d, J = 2.1 Hz, 1H), 6.89 (dd, J = (M + H)⁺. 1-carboxamide 3.1, 0.9 Hz,1H), 2.21 (s, 3H), 1.92 (tt, J = 8.5, 5.3 Hz, 1H), 1.67 (q, J = 3.7 Hz,2H), 1.09 (q, J = 3.7 Hz, 2H), 0.72-0.61 (m, 2H), 0.55-0.46 (m, 2H).Example 1-[5-methoxy-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.23 (ddd, J= MS GII-40 (pyrrolidin-1- 8.8, 1.7, 0.9 Hz, 1H), 8.90 (dd, J = 4.3, 1.7Hz, 1H), (ESI+) yl)pyridin-3-yl]-N- 8.30 (dd, J = 7.3, 1.2 Hz, 1H), 8.13(dt, J = 8.5, 1.1 Hz, m/z 453 (quinoline-5- 1H), 7.79 (dd, J = 8.5, 7.3Hz, 1H), 7.63-7.54 (m, (M + H)⁺. sulfonyl)cyclopropane- 2H), 7.17 (d, J= 3.0 Hz, 1H), 3.75 (s, 3H), 3.12 (q, J = 1-carboxamide 5.8, 4.6 Hz,4H), 1.55 (q, J = 3.7 Hz, 2H), 1.48-1.37 (m, 4H), 0.98 (q, J = 3.7 Hz,2H). Example 1-[2-(dimethylamino)- ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.04(dd, J = MS GII-41 5-methylpyridin-3-yl]- 8.8, 1.7 Hz, 1H), 8.96-8.91(m, 1H), 8.16-8.06 (m, (ESI+) N-(quinoline-5- 2H), 7.85-7.70 (m, 2H),7.61-7.53 (m, 1H), 7.31 (s, m/z 411 sulfonyl)cyclopropane- 1H), 2.74 (s,3H), 2.60 (s, 6H), 1.29 (q, J = 3.6 Hz, (M + H)⁺. 1-carboxamide 2H),0.89-0.83 (m, 2H). Example 1-[5-methoxy-2-(2- ¹H NMR (400 MHz,methanol-d₄) δ ppm 8.86 (dd, J = MS GII-42 methoxyethoxy)pyridin- 8.9,0.9 Hz, 1H), 8.40 (dd, J = 7.4, 1.3 Hz, 1H), 8.27 (ESI+) 3-yl]-N-(2-(dt, J = 8.5, 1.1 Hz, 1H), 7.90 (dd, J = 8.5, 7.4 Hz, 1H), m/z 472methylquinoline-5- 7.74 (d, J = 2.9 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H),7.24 (M + H)⁺. sulfonyl)cyclopropane- (d, J = 3.0 Hz, 1H), 4.01-3.94 (m,2H), 3.84 (s, 3H), 1-carboxamide 3.22 (s, 3H), 3.21-3.17 (m, 2H), 2.79(s, 3H), 1.43- 1.35 (m, 2H), 1.08-1.01 (m, 2H). Example N-(1H-indole-4-¹H NMR (400 MHz, methanol-d₄) δ ppm 7.78 (dd, J = MS GII-43sulfonyl)-1-[5- 7.5, 0.9 Hz, 1H), 7.76-7.70 (m, 2H), 7.45 (d, J = 3.1(ESI+) methoxy-2-(2- Hz, 1H), 7.31-7.21 (m, 2H), 6.74 (dd, J = 3.2, 0.9Hz, m/z 446 methoxyethoxy)pyridin- 1H), 4.06-3.99 (m, 2H), 3.83 (s, 3H),3.23 (s, 3H), (M + H)⁺. 3-yl]cyclopropane- 3.21-3.14 (m, 2H), 1.45-1.37(m, 2H), 1.04 (q, J = 1-carboxamide 4.5 Hz, 2H). Example1-[5-methoxy-2-(2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.03-8.96 MSGII-44 methoxyethoxy)pyridin- (m, 2H), 8.48 (dd, J = 7.5, 1.2 Hz, 1H),8.36 (d, J = 8.5 (ESI+) 3-yl]-N-(quinoline-5- Hz, 1H), 7.95 (dd, J =8.5, 7.4 Hz, 1H), 7.74 (d, J = 3.0 m/z 458 sulfonyl)cyclopropane- Hz,1H), 7.69-7.61 (m, 1H), 7.24 (d, J = 3.0 Hz, 1H), (M + H)⁺.1-carboxamide 4.01-3.94 (m, 2H), 3.84 (s, 3H), 3.25-3.17 (m, 5H),1.43-1.34 (m, 2H), 1.05 (q, J = 4.5 Hz, 2H). Example N-(1H-indole-4- ¹HNMR (400 MHz, methanol-d₄) δ ppm 7.79 (dd, J = MS GII-45 sulfonyl)-1-[2-7.6, 0.9 Hz, 1H), 7.75 (dt, J = 8.1, 0.9 Hz, 1H), 7.65 (s, (ESI+)methoxy-5-(2- 1H), 7.47 (d, J = 3.1 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H),m/z 446 methoxyethoxy)pyridin- 6.77 (dd, J = 3.1, 0.9 Hz, 1H), 6.68 (s,1H), 3.88 (s, (M + H)⁺. 4-yl]cyclopropane- 3H), 3.75-3.68 (m, 2H), 3.23(s, 3H), 3.11-3.04 (m, 1-carboxamide 2H), 1.45-1.38 (m, 2H), 1.10-1.03(m, 2H). Example 1-[2-methoxy-5-(2- ¹H NMR (400 MHz, methanol-d₄) δ ppm8.88 (dd, J = MS GII-46 methoxyethoxy)pyridin- 8.9, 0.9 Hz, 1H), 8.40(dd, J = 7.5, 1.2 Hz, 1H), 8.27 (ESI+) 4-yl]-N-(2- (dt, J = 8.5, 1.1 Hz,1H), 7.90 (dd, J = 8.5, 7.4 Hz, 1H), m/z 472 methylquinoline-5- 7.65 (s,1H), 7.57 (d, J = 8.9 Hz, 1H), 6.66 (s, 1H), (M + H)⁺.sulfonyl)cyclopropane- 3.88 (s, 3H), 3.75-3.68 (m, 2H), 3.22 (s, 3H),3.16- 1-carboxamide 3.09 (m, 2H), 2.80 (s, 3H), 1.42-1.35 (m, 2H), 1.10-1.03 (m, 2H). Example 1-[2-(dimethylamino)- ¹H NMR (400 MHz,chloroform-d) δ ppm 8.99 (dd, J = MS GII-47 5-ethylpyridin-3-yl]- 4.2,1.6 Hz, 1H), 8.93 (dt, J = 8.8, 1.2 Hz, 1H), 8.50 (ESI+) N-(quinoline-5-(dd, J = 7.5, 1.2 Hz, 1H), 8.38 (dt, J = 8.4, 1.1 Hz, 1H), m/z 425sulfonyl)cyclopropane- 8.18 (d, J = 2.3 Hz, 1H), 8.12 (s, 1H), 7.84 (dd,J = 8.5, (M + H)⁺. 1-carboxamide 7.5 Hz, 1H), 7.48 (dd, J = 8.7, 4.2 Hz,1H), 7.34 (d, J = 2.3 Hz, 1H), 5.30 (s, 1H), 2.94 (s, 6H), 2.58 (q, J =7.6 Hz, 2H), 1.55 (q, J = 4.2 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H), 1.11(q, J = 4.3 Hz, 2H). Example 1-[2-(dimethylamino)- ¹H NMR (400 MHz,chloroform-d) δ ppm 8.76 (dd, J = MS GII-48 5-ethylpyridin-3-yl]- 8.8,0.9 Hz, 1H), 8.41 (dd, J = 7.5, 1.2 Hz, 1H), 8.26 (ESI+)N-(2-methylquinoline- (dt, J = 8.5, 1.1 Hz, 1H), 8.19 (d, J = 2.3 Hz,1H), 7.78 m/z 439 5-sulfonyl)cyclopropane- (dd, J = 8.5, 7.5 Hz, 1H),7.36-7.29 (m, 2H), 2.92 (s, (M + H)⁺. 1-carboxamide 6H), 2.75 (s, 3H),2.61-2.54 (m, 2H), 1.54 (q, J = 4.2 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H),1.11 (q, J = 4.3 Hz, 2H). Example 1-[2-(dimethylamino)- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.60 (s, 1H), MS GII-49 5-ethylpyridin-3-yl]- 7.98 (d, J= 2.3 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.62- (ESI+) N-(1H-indole-4-7.54 (m, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.21 (t, J = m/z 413sulfonyl)cyclopropane- 7.8 Hz, 1H), 6.88-6.82 (m, 1H), 2.52 (s, 6H),2.52- (M + H)⁺. 1-carboxamide 2.48 (m, 2H), 1.37 (q, J = 4.3 Hz, 2H),1.17 (t, J = 7.6 Hz, 3H), 1.10 (q, J = 4.4 Hz, 2H). Example 1-[2-(2- ¹HNMR (400 MHz, methanol-d₄) δ ppm 8.83 (dd, J = MS GII-50methoxyethoxy)-5- 8.9, 0.9 Hz, 1H), 8.37 (dd, J = 7.5, 1.2 Hz, 1H), 8.24(ESI+) methylpyridin-3-yl]- (dt, J = 8.5, 1.1 Hz, 1H), 7.92-7.83 (m,2H), 7.52 (d, J = m/z 456 N-(2-methylquinoline- 8.9 Hz, 1H), 7.42-7.37(m, 1H), 4.01-3.94 (m, (M + H)⁺. 5-sulfonyl)cyclopropane- 2H), 3.19 (s,3H), 3.19-3.15 (m, 2H), 2.77 (s, 3H), 1-carboxamide 2.24 (s, 3H), 1.36(q, J = 4.4 Hz, 2H), 1.04-0.98 (m, 2H). Example 1-{2-(dimethylamino)- ¹HNMR (400 MHz, methanol-d₄) δ ppm 9.08 (dt, J = MS GII-51 6-[(propan-2-8.7, 1.3 Hz, 1H), 9.02-8.94 (m, 1H), 8.44 (dd, J = 7.4, (ESI+)yl)oxy]pyridin-3-yl}- 1.3 Hz, 1H), 8.30 (dt, J = 8.5, 1.1 Hz, 1H), 7.91(dd, J = m/z 455 N-(quinoline-5- 8.6, 7.5 Hz, 1H), 7.64 (dd, J = 8.8,4.3 Hz, 1H), 7.42 (M + H)⁺. sulfonyl)cyclopropane- (d, J = 8.3 Hz, 1H),6.34 (d, J = 8.3 Hz, 1H), 5.26 1-carboxamide (hept, J = 6.2 Hz, 1H),2.96 (s, 1H), 2.81 (s, 6H), 1.43 (q, J = 4.1 Hz, 2H), 1.35 (d, J = 6.2Hz, 6H), 1.10 (q, J = 4.1 Hz, 2H). Example 1-[2-(2- ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.04-8.96 MS GII-52 methoxyethoxy)-5- (m, 2H), 8.49(dd, J = 7.5, 1.3 Hz, 1H), 8.37 (dt, J = (ESI+) methylpyridin-3-yl]-8.5, 1.1 Hz, 1H), 7.95 (dd, J = 8.5, 7.4 Hz, 1H), 7.89 m/z 442N-(quinoline-5- (dd, J = 2.4, 1.0 Hz, 1H), 7.65 (dd, J = 8.7, 4.4 Hz,(M + H)⁺. sulfonyl)cyclopropane- 1H), 7.45-7.40 (m, 1H), 4.03-3.96 (m,2H), 3.25- 1-carboxamide 3.17 (m, 5H), 2.28 (s, 3H), 1.41-1.35 (m, 2H),1.07- 1.00 (m, 2H). Example N-(1H-indole-4- ¹H NMR (400 MHz,methanol-d₄) δ ppm 7.72 (dd, J = MS GII-53 sulfonyl)-1-[2-(2- 2.4, 1.0Hz, 1H), 7.64 (dd, J = 7.5, 0.9 Hz, 1H), 7.52 (ESI+) methoxyethoxy)-5-(dt, J = 8.1, 0.9 Hz, 1H), 7.40-7.35 (m, 1H), 7.31 (d, J = m/z 430methylpyridin-3- 3.2 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.83 (dd, J =(M + H)⁺. yl]cyclopropane-1- 3.1, 0.9 Hz, 1H), 4.17-4.09 (m, 2H),3.38-3.34 (m, carboxamide 3H), 3.29 (s, 3H), 2.22 (d, J = 0.7 Hz, 3H),1.47 (q, J = 3.9 Hz, 2H), 0.85 (q, J = 3.9 Hz, 2H). Example1-(5-ethyl-2-{4- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.19 (ddd, J = MSGII-54 [(propan-2- 8.7, 1.7, 0.9 Hz, 1H), 8.88 (dd, J = 4.3, 1.7 Hz,1H), (ESI+) yl)oxy]piperidin-1- 8.27 (dd, J = 7.3, 1.2 Hz, 1H), 8.12(dt, J = 8.5, 1.1 Hz, m/z 523 yl}pyridin-3-yl)-N- 1H), 7.84-7.74 (m,2H), 7.58 (dd, J = 8.7, 4.3 Hz, (M + H)⁺. (quinoline-5- 1H), 7.45 (d, J= 2.4 Hz, 1H), 3.68 (hept, J = 6.1 Hz, sulfonyl)cyclopropane- 1H),3.39-3.22 (m, 3H), 2.61 (ddd, J = 12.9, 10.2, 2.8 1-carboxamide Hz, 2H),2.53 (q, J = 7.6 Hz, 2H), 1.50 (dq, J = 14.3, 3.8 Hz, 4H), 1.32 (dtd, J= 12.9, 9.5, 3.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H), 1.13 (d, J = 6.1 Hz,6H), 0.97 (q, J = 3.7 Hz, 2H). Example 1-(5-ethyl-2-{4- ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.05 (dd, J = MS GII-55 [(propan-2- 8.9, 0.8 Hz, 1H),8.20 (dd, J = 7.3, 1.2 Hz, 1H), 8.03 (ESI+) yl)oxy]piperidin-1- (dt, J =8.5, 1.1 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.72 m/z 537yl}pyridin-3-yl)-N-(2- (dd, J = 8.5, 7.3 Hz, 1H), 7.49-7.43 (m, 2H),3.69 (M + H)⁺. methylquinoline-5- (hept, J = 6.1 Hz, 1H), 3.35 (dt, J =8.7, 4.2 Hz, 1H), sulfonyl)cyclopropane- 3.29-3.22 (m, 2H), 2.74 (s,3H), 2.60 (ddd, J = 12.9, 1-carboxamide 10.3, 2.7 Hz, 2H), 2.53 (q, J =7.6 Hz, 2H), 1.50 (dq, J = 14.7, 4.0 Hz, 4H), 1.37-1.29 (m, 2H), 1.18(t, J = 7.6 Hz, 3H), 1.14 (d, J = 6.1 Hz, 6H), 0.97 (q, J = 3.7 Hz, 2H).Example 1-[5-ethyl-2-(2- ¹H NMR (400 MHz, chloroform-d) δ ppm 8.70 (d, J= MS GII-56 methoxyethoxy)pyridin- 8.9 Hz, 1H), 8.39-8.32 (m, 1H), 8.23(dt, J = 8.5, 1.1 (ESI+) 3-yl]-N-(2- Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H),7.78-7.69 (m, 1H), m/z 470 methylquinoline-5- 7.32 (d, J = 8.9 Hz, 1H),7.25 (d, J = 2.4 Hz, 1H), 4.42- (M + H)⁺. sulfonyl)cyclopropane- 4.35(m, 2H), 3.56-3.49 (m, 2H), 3.32 (s, 3H), 2.74 1-carboxamide (s, 3H),2.50 (q, J = 7.6 Hz, 2H), 1.45 (q, J = 4.3 Hz, 2H), 1.16 (t, J = 7.6 Hz,3H), 0.94 (q, J = 4.4 Hz, 2H). Example 1-[5-ethyl-2-(4- ¹H NMR (400 MHz,chloroform-d) δ ppm 8.96 (dd, J = MS GII-57 methoxypiperidin-1- 4.2, 1.6Hz, 1H), 8.83 (ddd, J = 8.8, 1.7, 0.9 Hz, 1H), (ESI+)yl)pyridin-3-yl]-N- 8.50 (dd, J = 1.5, 1.3 Hz, 1H), 8.35 (dt, J = 8.5,1.1 Hz, m/z 495 (quinoline-5- 1H), 8.23-8.17 (m, 1H), 7.82 (dd, J = 8.5,7.4 Hz, (M + H)⁺. sulfonyl)cyclopropane- 1H), 7.42 (dd, J = 8.8, 4.2 Hz,1H), 7.30 (d, J = 2.4 Hz, 1-carboxamide 1H), 3.45-3.37 (m, 3H), 3.37 (s,3H), 3.02 (ddd, J = 12.2, 8.6, 3.3 Hz, 2H), 2.58 (q, J = 7.6 Hz, 2H),2.03- 1.91 (m, 2H), 1.74 (dtd, J = 12.7, 8.1, 3.5 Hz, 2H), 1.55 (q, J =4.2 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H), 1.12 (q, J = 4.3 Hz, 2H). Example1-[5-ethyl-2-(4- ¹H NMR (400 MHz, chloroform-d) δ ppm 8.57 (s, 1H), MSGII-58 methoxypiperidin-1- 8.16 (d, J = 2.3 Hz, 1H), 7.92 (dd, J = 7.6,0.9 Hz, 1H), (ESI+) yl)pyridin-3-yl]-N- 7.64 (dt, J = 8.0, 1.0 Hz, 1H),7.35 (dd, J = 2.8, 1.2 Hz, m/z 483 (1H-indole-4- 1H), 7.30 (t, J = 7.9Hz, 1H), 6.82 (ddd, J = 3.1, 2.0, (M + H)⁺. sulfonyl)cyclopropane- 0.9Hz, 1H), 3.33 (s, 3H), 3.28 (td, J = 8.1, 4.1 Hz, 1-carboxamide 2H),2.87 (ddd, J = 12.4, 9.2, 3.1 Hz, 2H), 2.60 (q, J = 7.6 Hz, 2H),1.85-1.76 (m, 2H), 1.56 (dq, J = 12.0, 4.0 Hz, 5H), 1.24 (t, J = 7.6 Hz,3H), 1.14 (q, J = 4.2 Hz, 2H). Example 1-{5-ethyl-2-[4- ¹H NMR (400 MHz,chloroform-d) δ ppm 8.96 (dd, J = MS GII-59 (methoxymethyl)piperidin-4.3, 1.6 Hz, 1H), 8.92 (dt, J = 8.8, 1.3 Hz, 1H), 8.48 (ESI+)1-yl]pyridin-3- (dd, J = 7.5, 1.2 Hz, 1H), 8.37 (dt, J = 8.5, 1.1 Hz,1H), m/z 509 yl}-N-(quinoline-5- 8.13 (d, J = 2.3 Hz, 1H), 7.83 (dd, J =8.5, 7.4 Hz, 1H), (M + H)⁺. sulfonyl)cyclopropane- 7.45 (dd, J = 8.8,4.3 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 1-carboxamide 3.47 (dd, J = 13.0,3.5 Hz, 2H), 3.34 (s, 3H), 3.23 (d, J = 6.1 Hz, 2H), 2.95 (td, J = 12.4,2.4 Hz, 2H), 2.55 (q, J = 7.6 Hz, 2H), 1.80-1.66 (m, 3H), 1.55 (q, J =4.3 Hz, 2H), 1.48-1.33 (m, 2H), 1.18 (t, J = 7.6 Hz, 3H), 1.09 (q, J =4.3 Hz, 2H).

TABLE 5 NMR MS Example 1-[3-chloro-5- ¹H NMR (400 MHz, methanol-d₄) δppm 9.08 (dt, J = LC/MS GIII-1 (trifluoromethyl)pyridin- 8.8, 1.2 Hz,1H), 8.99 (dd, J = 4.3, 1.6 Hz, 1H), 8.73 (dt, (ESI+)2-yl]-N-(quinoline-5- J = 2.8, 1.4 Hz, 1H), 8.46 (dd, J = 7.4, 1.2 Hz,1H), 8.33 m/z 456 sulfonyl)cyclopropane- (dt, J = 8.5, 1.1 Hz, 1H), 8.17(dd, J = 32.2, 2.1 Hz, 1H), and 458 1-carboxamide 7.92 (dd, J = 8.5, 7.4Hz, 1H), 7.69 (dd, J = 8.8, 4.3 Hz, (M + H)⁺. 1H), 1.53 (q, J = 4.4, 4.0Hz, 2H), 1.38 (q, J = 4.8, 4.4 Hz, 2H). Example 1-[5-chloro-2- ¹H NMR(400 MHz, chloroform-d) δ ppm 9.10 (dd, J = LC/MS GIII-2(trifluoromethyl)pyridin- 4.2, 1.6 Hz, 1H), 8.76 (dd, J = 8.7, 1.5 Hz,1H), 8.55- (ESI+) 3-yl]-N-(quinoline-5- 8.47 (m, 2H), 7.90 (dd, J = 8.5,7.5 Hz, 1H), 7.81 (d, J = m/z 456 sulfonyl)cyclopropane- 2.2 Hz, 1H),7.61 (dd, J = 8.8, 4.2 Hz, 1H), 7.25 (s, 1H), (M + H)⁺. 1-carboxamide1.75-1.64 (m, 2H), 1.24-1.13 (m, 2H) Example N-(1H-indole-4- ¹H NMR (400MHz, methanol-d₄) δ ppm 7.74 (s, 1H), LC/MS GIII-3 sulfonyl)-1-{6- 7.61(dd, J = 7.5, 1.0 Hz, 1H), 7.50 (dt, J = 8.1, 1.0 Hz, (ESI+)methoxy-4-[(propan- 1H), 7.31 (d, J = 3.2 Hz, 1H), 7.12 (t, J = 7.8 Hz,1H), m/z 430 2-yl)oxy]pyridin-3- 6.90 (dd, J = 3.1, 1.0 Hz, 1H), 6.18(s, 1H), 4.51 (hept, J = (M + H)⁺. yl}cyclopropane-1- 6.0 Hz, 1H), 3.85(s, 3H), 1.50 (q, J = 3.8 Hz, 2H), carboxamide 1.13 (d, J = 6.0 Hz, 6H),0.82 (q, J = 3.8 Hz, 2H). Example 1-(3-cyclopropyl-5- ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.19 (ddd, J = LC/MS GIII-4 methylpyridin-2-yl)- 8.8,1.7, 0.9 Hz, 1H), 8.87 (dd, J = 4.3, 1.7 Hz, 1H), (ESI+) N-(quinoline-5-8.28 (dd, J = 7.3, 1.3 Hz, 1H), 8.10 (dt, J = 8.5, 1.1 Hz, m/z 408sulfonyl)cyclopropane- 1H), 7.94-7.87 (m, 1H), 7.77 (dd, J = 8.5, 7.3Hz, 1H), (M + H)⁺. 1-carboxamide 7.57 (dd, J = 8.7, 4.3 Hz, 1H), 6.94(d, J = 2.1 Hz, 1H), 2.22 (s, 3H), 1.78 (tt, J = 8.4, 5.3 Hz, 1H), 1.57(q, J = 3.7 Hz, 2H), 1.07 (q, J = 3.7 Hz, 2H), 0.63-0.53 (m, 2H),0.51-0.43 (m, 2H). Example 1-[2-chloro-5-(2- ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.07 (dt, J = LC/MS GIII-5 methylpropoxy)pyridin-8.8, 1.2 Hz, 1H), 9.00 (dd, J = 4.3, 1.6 Hz, 1H), 8.46 (ESI+)3-yl]-N-(quinoline-5- (dd, J = 7.5, 1.2 Hz, 1H), 8.34 (dt, J = 8.5, 1.1Hz, 1H), m/z 460 sulfonyl)cyclopropane- 7.99 (d, J = 2.9 Hz, 1H), 7.92(dd, J = 8.5, 7.4 Hz, 1H), and 462 1-carboxamide 7.68 (dd, J = 8.8, 4.3Hz, 1H), 7.39 (d, J = 2.9 Hz, 1H), (M + H)⁺. 3.85 (d, J = 6.4 Hz, 2H),2.10 (dp, J = 13.2, 6.6 Hz, 1H), 1.55 (q, J = 4.5 Hz, 2H), 1.17 (q, J =4.5 Hz, 2H), 1.06 (d, J = 6.7 Hz, 6H).. Example 1-(4-ethylpyridin-3- ¹HNMR (400 MHz, methanol-d₄) δ ppm 9.14 (ddd, J = LC/MS GIII-6yl)-N-(quinoline-5- 8.8, 1.7, 0.9 Hz, 1H), 8.91 (dd, J = 4.3, 1.7 Hz,1H), (ESI+) sulfonyl)cyclopropane- 8.24 (dd, J = 3.8, 1.4 Hz, 2H), 8.14(dt, J = 8.5, 1.1 Hz, m/z 381 1-carboxamide 1H), 7.79 (dd, J = 8.5, 7.3Hz, 1H), 7.59 (dd, J = 8.7, 4.3 (M + H)⁺. Hz, 1H), 7.22-7.10 (m, 1H),2.44 (q, J = 7.6 Hz, 2H), 1.58-1.50 (m, 2H), 1.02-0.88 (m, 5H). Example1-(2-fluoro-5- ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.84 (s, 1H), LC/MSGIII-7 methylpyridin-4-yl)- 7.24 (dd, J = 7.8, 1.2 Hz, 1H), 6.96-6.86(m, 2H), 6.59 (ESI+) N-(1,2,3,4- (dd, J = 8.0, 1.3 Hz, 1H), 3.26-3.19(m, 2H), 3.08- m/z 390 tetrahydroquinoline-5- 2.98 (m, 6H), 2.25 (d, J =1.0 Hz, 3H), 1.89-1.79 (m, (M + H)⁺. sulfonyl)cyclopropane- 2H), 1.56(q, J = 3.8 Hz, 2H), 0.94 (q, J = 3.9 Hz, 2H). 1-carboxamide Example1-(6-methoxy-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.15 (ddd, J = LC/MSGIII-8 methylpyridin-3-yl)- 8.8, 1.7, 0.9 Hz, 1H), 8.90 (dd, J = 4.3,1.7 Hz, 1H), (ESI+) N-(quinoline-5- 8.26 (dd, J = 7.3, 1.2 Hz, 1H), 8.14(dt, J = 8.5, 1.1 Hz, m/z 398 sulfonyl)cyclopropane- 1H), 7.80 (dd, J =8.5, 7.3 Hz, 1H), 7.58 (dd, J = 8.7, 4.3 (M + H)⁺. 1-carboxamide Hz,1H), 7.43 (d, J = 8.3 Hz, 1H), 6.51 (dd, J = 8.3, 0.7 Hz, 1H), 3.85 (s,3H), 2.14 (s, 3H), 1.48 (q, J = 3.4 Hz, 2H), 0.85 (q, J = 3.4 Hz, 2H).Example 1-[5-cyclopropyl-2-(4- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.21(ddd, J = LC/MS GIII-9 methylpiperazin-1- 8.7, 1.7, 0.9 Hz, 1H), 8.91(dd, J = 4.3, 1.7 Hz, 1H), (ESI+) yl)pyridin-3-yl]-N- 8.30 (dd, J = 7.3,1.2 Hz, 1H), 8.13 (dt, J = 8.5, 1.1 Hz, m/z 492 (quinoline-5- 1H),7.85-7.75 (m, 2H), 7.62 (dd, J = 8.7, 4.3 Hz, 1H), (M + H)⁺.sulfonyl)cyclopropane- 7.27 (d, J = 2.4 Hz, 1H), 3.05-2.98 (m, 4H), ),2.35- 1-carboxamide 2.17 (m, 7H), 1.84 (tt, J = 8.5, 5.1 Hz, 1H), 1.51(q, J = 3.7 Hz, 2H), 1.00-0.87 (m, 4H), 0.68-0.58 (m, 2H). Example1-[5-cyclopropyl-2- LC/MS GIII-10 (trifluoromethyl)pyridin- (ESI+)3-yl]-N-(quinoline-5- m/z 462 sulfonyl)cyclopropane- (M + H)⁺.1-carboxamide Example 1-[2-methoxy-5-(2- ¹H NMR (400 MHz, methanol-d₄) δppm 9.07-8.97 LC/MS GIII-11 methoxyethoxy)pyridin- (m, 2H), 8.48 (dd, J= 7.4, 1.2 Hz, 1H), 8.36 (d, J = 8.5 (ESI+) 4-yl]-N-(quinoline-5- Hz,1H), 7.95 (dd, J = 8.5, 7.4 Hz, 1H), 7.73-7.60 (m, m/z 458sulfonyl)cyclopropane- 2H), 6.67 (s, 1H), 3.89 (s, 3H), 3.75-3.60 (m,2H), (M + H)⁺. 1-carboxamide 3.21 (s, 3H), 3.17-3.07 (m, 2H), 1.42-1.34(m, 2H), 1.06 (q, J = 4.5 Hz, 2H). Example 1-(2,4- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.42 (s, 1H), LC/MS GIII-12 dimethoxypyrimidin- 8.17 (s,1H), 7.07-6.96 (m, 2H), 6.70 (dd, J = 6.9, 2.5 (ESI+) 5-yl)-N-(1,2,3,4-Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.19 (t, J = 6.1 Hz, m/z 419tetrahydroquinoline-5- 2H), 2.88 (t, J = 6.4 Hz, 2H), 1.78 (p, J = 6.1Hz, 2H), (M + H)⁺. sulfonyl)cyclopropane- 1.33 (q, J = 4.1 Hz, 2H), 1.06(q, J = 4.2 Hz, 2H). 1-carboxamide Example 1-{2-chloro-5- ¹H NMR (400MHz, methanol-d₄) δ ppm 9.11-9.03 LC/MS GIII-13 [(propan-2- (m, 1H),8.99 (dd, J = 4.3, 1.6 Hz, 1H), 8.45 (dd, J = (ESI+)yl)oxy]pyridin-3-yl}- 7.4, 1.2 Hz, 1H), 8.33 (dt, J = 8.6, 1.1 Hz, 1H),7.97- m/z 446 N-(quinoline-5- 7.86 (m, 2H), 7.68 (dd, J = 8.8, 4.3 Hz,1H), 7.35 (d, J = and 448 sulfonyl)cyclopropane- 2.9 Hz, 1H), 4.67 (p, J= 6.0 Hz, 1H), 1.54 (q, J = 4.5 (M + H)⁺. 1-carboxamide Hz, 2H), 1.34(d, J = 6.0 Hz, 6H), 1.15 (q, J = 4.5 Hz, 2H). Example 1-[5-(2,2- ¹H NMR(400 MHz, chloroform-d) δ ppm 8.72 (d, J = LC/MS GIII-14difluoroethoxy)-2- 8.9 Hz, 1H), 8.45-8.39 (m, 1H), 8.33 (d, J = 8.4 Hz,(ESI+) methoxypyridin-4-yl]- 1H), 7.82 (dd, J = 8.5, 7.5 Hz, 1H), 7.78(s, 1H), 7.44 (d, m/z 478 N-(2-methylquinoline- J = 8.9 Hz, 1H), 6.64(s, 1H), 5.63 (tt, J = 54.9, 4.0 Hz, (M + H)⁺. 5-sulfonyl)cyclopropane-2H), 4.01 (td, J = 12.7, 4.1 Hz, 2H), 3.95 (s, 3H), 2.81 1-carboxamide(s, 3H), 1.54 (q, J = 4.4 Hz, 2H), 1.04 (q, J = 4.5 Hz, 2H). Example1-(6-methoxy-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.48 (d, J = LC/MSGIII-15 methylpyridin-3-yl)- 8.4 Hz, 1H), 7.19 (dd, J = 7.8, 1.3 Hz,1H), 6.90 (t, J = (ESI+) N-(1,2,3,4- 7.9 Hz, 1H), 6.57 (dd, J = 8.1, 1.2Hz, 1H), 6.52 (dd, J = m/z 402 tetrahydroquinoline-5- 8.3, 0.7 Hz, 1H),3.85 (s, 3H), 3.23-3.16 (m, 2H), 3.03 (M + H)⁺. sulfonyl)cyclopropane-(t, J = 6.4 Hz, 2H), 2.39 (s, 3H), 1.88-1.74 (m, 2H), 1-carboxamide 1.55(q, J = 3.4 Hz, 2H), 0.89 (q, J = 3.5 Hz, 2H). Example 1-(2-fluoro-5- ¹HNMR (400 MHz, methanol-d₄) δ ppm 9.11 (ddd, J = LC/MS GIII-16methylpyridin-4-yl)- 8.7, 1.7, 0.9 Hz, 1H), 8.90 (dd, J = 4.2, 1.7 Hz,1H), (ESI+) N-(quinoline-5- 8.28 (dd, J = 7.3, 1.2 Hz, 1H), 8.14 (dt, J= 8.5, 1.1 Hz, m/z 386 sulfonyl)cyclopropane- 1H), 7.84-7.76 (m, 2H),7.58 (dd, J = 8.7, 4.3 Hz, 1H), (M + H)⁺. 1-carboxamide 6.84 (d, J = 1.4Hz, 1H), 1.97 (t, J = 1.0 Hz, 3H), 1.48 (q, J = 3.8 Hz, 2H), 0.90 (q, J= 3.8 Hz, 2H). Example 1-(6-methoxy-4- ¹H NMR (400 MHz, methanol-d₄) δppm 7.85 (s, 1H), LC/MS GIII-17 methylpyridin-3-yl)- 7.20 (dd, J = 7.8,1.3 Hz, 1H), 6.89 (t, J = 7.9 Hz, 1H), (ESI+) N-(1,2,3,4- 6.60-6.53 (m,2H), 3.84 (s, 3H), 3.24-3.17 (m, 2H), m/z 402 tetrahydroquinoline-5-3.05 (t, J = 6.4 Hz, 2H), 2.27 (d, J = 0.8 Hz, 3H), 1.88- (M + H)⁺.sulfonyl)cyclopropane- 1.77 (m, 2H), 1.54 (d, J = 3.3 Hz, 2H), 0.89 (q,J = 3.3 1-carboxamide Hz, 2H). Example 1-[5-(2,2- ¹H NMR (400 MHz,chloroform-d) δ ppm 9.06 (dd, J = LC/MS GIII-18 difluoroethoxy)-2- 4.2,1.6 Hz, 1H), 8.83 (ddd, J = 8.8, 1.6, 0.9 Hz, 1H), (ESI+)methoxypyridin-4-yl]- 8.53 (dd, J = 7.4, 1.3 Hz, 1H), 8.44 (dt, J = 8.4,1.1 Hz, m/z 464 N-(quinoline-5- 1H), 7.88 (dd, J = 8.5, 7.5 Hz, 1H),7.76 (s, 1H), 7.57 (M + H)⁺. sulfonyl)cyclopropane- (dd, J = 8.8, 4.2Hz, 1H), 6.61 (s, 1H), 5.63 (tt, J = 54.9, 1-carboxamide 4.0 Hz, 1H),3.98 (td, J = 12.7, 4.0 Hz, 2H), 3.90 (s, 3H), 1.54 (q, J = 4.5 Hz, 2H),1.04 (q, J = 4.5 Hz, 2H). Example 1-[5- ¹H NMR (400 MHz, chloroform-d) δppm 9.04 (dd, J = LC/MS GIII-19 (difluoromethoxy)-2- 4.2, 1.6 Hz, 1H),8.83 (ddd, J = 8.7, 1.6, 0.9 Hz, 1H), (ESI+) methoxypyridin-4-yl]- 8.51(dd, J = 7.5, 1.3 Hz, 1H), 8.42 (dt, J = 8.5, 1.1 Hz, m/z 450N-(quinoline-5- 1H), 7.99 (d, J = 1.3 Hz, 1H), 7.86 (dd, J = 8.5, 7.5Hz, (M + H)⁺. sulfonyl)cyclopropane- 1H), 7.57 (dd, J = 8.8, 4.2 Hz,1H), 6.61 (s, 1H), 6.14 (t, 1-carboxamide J = 72.5 Hz, 1H), 3.84 (s,3H), 1.54 (q, J = 4.5 Hz, 2H), 1.06 (q, J = 4.5 Hz, 2H). Example1-[5-cyclopropyl-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.02 (dd, J =LC/MS GIII-20 (morpholin-4- 8.9, 0.9 Hz, 1H), 8.18 (dd, J = 12, 1.2 Hz,1H), 8.04 (dt, (ESI+) yl)pyridin-3-yl]-N-(2- J = 8.5, 1.1 Hz, 1H), 7.82(d, J = 2.4 Hz, 1H), 7.72 (dd, m/z 493 methylquinoline-5- J = 8.5, 7.3Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.25 (d, J = (M + H)⁺.sulfonyl)cyclopropane- 2.4 Hz, 1H), 3.50-3.43 (m, 4H), 2.95-2.89 (m,4H), 1-carboxamide 2.74 (s, 3H), 1.82 (tt, J = 8.4, 5.1 Hz, 1H), 1.48(q, J = 3.7 Hz, 2H), 0.98 (q, J = 3.8 Hz, 2H), 0.95-0.86 (m, 2H),0.64-0.55 (m, 2H). Example 1-[2-chloro-6- ¹H NMR (400 MHz, methanol-d₄)δ ppm 8.75-8.67 LC/MS GIII-21 (trifluoromethyl)pyridin- (m, 1H), 8.21(dd, J = 12, 1.2 Hz, 1H), 7.99 (d, J = 8.2 (ESI+) 3-yl]-N- Hz, 1H),7.95-7.85 (m, 2H), 7.66 (d, J = 7.8 Hz, 1H), m/z 455 (naphthalene-1-7.59-7.46 (m, 3H), 1.57 (q, J = 4.0 Hz, 2H), 0.98 (q, J = and 457sulfonyl)cyclopropane- 4.0 Hz, 2H). (M + H)⁺. 1-carboxamide Example1-[5- ¹H NMR (400 MHz, chloroform-d) δ ppm 8.91 (dd, J = LC/MS GIII-22(difluoromethoxy)-2- 8.8, 0.8 Hz, 1H), 8.09 (ddd, J = 8.5, 3.0, 1.1 Hz,2H), (ESI+) methoxypyridin-4-yl]- 7.86 (d, J = 1.2 Hz, 1H), 7.60 (dd, J= 8.4, 7.3 Hz, 1H), m/z 464 N-(2-methylquinoline- 7.29 (d, J = 8.8 Hz,1H), 6.62-6.23 (m, 2H), 3.90 (s, (M + H)⁺. 5-sulfonyl)cyclopropane- 3H),2.77 (s, 3H), 1.49 (q, J = 4.0 Hz, 2H), 0.92 (q, J = 1-carboxamide 4.0Hz, 2H). Example 1-[5-ethyl-2- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.19(dd, J = LC/MS GIII-23 (morpholin-4- 8.9, 1.7 Hz, 1H), 8.91 (dd, J =4.3, 1.7 Hz, 1H), 8.32- (ESI+) yl)pyridin-3-yl]-N- 8.25 (m, 1H), 8.15(d, J = 8.5 Hz, 1H), 7.88 (d, J = 2.3 m/z 467 (quinoline-5- Hz, 1H),7.84-7.76 (m, 1H), 7.60 (dd, J = 8.7, 4.3 Hz, (M + H)⁺.sulfonyl)cyclopropane- 1H), 7.47 (d, J = 2.4 Hz, 1H), 3.52-3.45 (m, 4H),2.99- 1-carboxamide 2.92 (m, 4H), 2.56 (q, J = 7.6 Hz, 2H), 1.52 (q, J =3.7 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H), 1.02 (q, J = 3.8 Hz, 2H). Example1-(2,4- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.14 (ddd, J = LC/MS GIII-24dimethoxypyrimidin- 8.7, 1.7, 0.9 Hz, 1H), 8.90 (dd, J = 4.3, 1.7 Hz,1H), (ESI+) 5-yl)-N-(quninoline-5- 8.27 (dd, J = 7.3, 1.2 Hz, 1H), 8.14(dt, J = 8.5, 1.1 Hz, m/z 414 sulfonyl)cyclopropane- 1H), 7.96 (s, 1H),7.80 (dd, J = 8.5, 7.3 Hz, 1H), 7.60 (M + H)⁺. 1-carboxamide (dd, J =8.7, 4.3 Hz, 1H), 3.95 (s, 3H), 3.71 (s, 3H), 1.36 (q, J = 3.9 Hz, 2H),0.82 (q, J = 3.9 Hz, 2H). Example 1-[5-cyclopropyl-2- ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.18 (ddd, J = LC/MS GIII-25 (morpholin-4- 8.8, 1.7,0.9 Hz, 1H), 8.91 (dd, J = 4.3, 1.7 Hz, 1H), (ESI+) yl)pyridin-3-yl]-N-8.28 (dd, J = 7.3, 1.2 Hz, 1H), 8.14 (dt, J = 8.5, 1.1 Hz, m/z 479(quinoline-5- 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.80 (dd, J = 8.5, 7.3 Hz,(M + H)⁺. sulfonyl)cyclopropane- 1H), 7.60 (dd, J = 8.7, 4.2 Hz, 1H),7.27 (d, J = 2.5 Hz, 1-carboxamide 1H), 3.51-3.44 (m, 4H), 2.97-2.92 (m,4H), 1.84 (tt, J = 8.4, 5.1 Hz, 1H), 1.50 (q, J = 3.7 Hz, 2H), 1.00 (q,J = 3.8 Hz, 2H), 0.97-0.91 (m, 2H), 0.66-0.58 (m, 2H). Example1-[5-methyl-2-(4- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.21 (d, J = LC/MSGIII-26 methylpiperazin-1- 8.7 Hz, 1H), 8.91 (dd, J = 4.3, 1.7 Hz, 1H),8.34-8.28 (ESI+) yl)pyridin-3-yl]-N- (m, 1H), 8.14 (d, J = 8.4 Hz, 1H),7.88 (d, J = 2.3 Hz, m/z 466 (quinoline-5- 1H), 7.85-7.77 (m, 1H), 7.61(dd, J = 8.7, 4.3 Hz, 1H), (M + H)⁺. sulfonyl)cyclopropane- 7.43 (d, J =2.3 Hz, 1H), 3.18-3.08 (m, 4H), 2.70- 1-carboxamide 2.52 (m, 4H),2.52-2.40 (m, 3H), 2.24 (s, 3H), 1.47 (q, J = 3.8 Hz, 2H), 0.97 (q, J =3.8 Hz, 2H). Example 1-[5-cyclopropyl-2-(4- ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.08-8.99 LC/MS GIII-27 methylpiperazin-1- (m, 1H),8.21 (dd, J = 7.3, 1.2 Hz, 1H), 8.04 (dt, J = 8.5, (ESI+)yl)pyridin-3-yl]-N-(2- 1.1 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.73 (dd,J = 8.5, m/z 506 methylquinoline-5- 7.3 Hz, 1H), 7.49 (d, J = 8.9 Hz,1H), 7.23 (d, J = 2.4 (M + H)⁺. sulfonyl)cyclopropane- Hz, 1H),3.13-3.04 (m, 4H), 2.75 (s, 3H), 2.65-2.49 1-carboxamide (m, 4H), 2.43(s, 3H), 1.83 (ddd, J = 13.6, 8.5, 5.1 Hz, 1H), 1.47 (q, J = 3.7 Hz,2H), 0.98-0.87 (m, 4H), 0.68- 0.58 (m, 2H). Example 1-[2-chloro-6- ¹HNMR (400 MHz, methanol-d₄) δ ppm 7.94 (d, J = LC/MS GIII-28(trifluoromethyl)pyridin- 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.26(dd, J = 7.8, (ESI+) 3-yl]-N-(1,2,3,4- 1.2 Hz, 1H), 6.92 (t, J = 7.9 Hz,1H), 6.59 (dd, J = 8.0, m/z 460 tetrahydroquinoline-5- 1.2 Hz, 1H),3.26-3.19 (m, 2H), 3.10-3.06 (m, 2H), and 462 sulfonyl)cyclopropane-1.87 (p, J = 6.3 Hz, 2H), 1.63 (q, J = 3.9 Hz, 2H), 1.02 (M + H)⁺.1-carboxamide (q, J = 4.0 Hz, 2H). Example 1-[2-chloro-6- ¹H NMR (400MHz, methanol-d₄) δ ppm 9.14 (dt, J = LC/MS GIII-29(trifluoromethyl)pyridin- 8.5, 1.4 Hz, 1H), 8.89 (dd, J = 4.3, 1.7 Hz,1H), 8.29 (ESI+) 3-yl]-N-(quinoline-5- (dd, J = 7.4, 1.2 Hz, 1H), 8.14(dt, J = 8.5, 1.1 Hz, 1H), m/z 456 sulfonyl)cyclopropane- 7.90 (d, J =7.8 Hz, 1H), 7.80 (dd, J = 8.5, 7.3 Hz, 1H), and 458 1-carboxamide 7.67(d, J = 7.8 Hz, 1H), 7.58 (dd, J = 8.7, 4.3 Hz, 1H), (M + H)⁺. 1.55 (q,J = 3.9 Hz, 2H), 0.98 (q, J = 4.0 Hz, 2H). Example 1-(6-amino-2- ¹H NMR(400 MHz, methanol-d₄) δ ppm 9.23-9.15 LC/MS GIII-30methoxypyridin-3-yl)- (m, 1H), 8.89 (dd, J = 4.3, 1.6 Hz, 1H), 8.27 (dd,J = (ESI+) N-(quinoline-5- 7.3, 1.2 Hz, 1H), 8.13 (dt, J = 8.5, 1.1 Hz,1H), 7.80 (dd, m/z 399 sulfonyl)cyclopropane- J = 8.5, 7.3 Hz, 1H), 7.59(dd, J = 8.7, 4.3 Hz, 1H), 7.17 (M + H)⁺. 1-carboxamide (d, J = 7.9 Hz,1H), 6.02 (d, J = 7.9 Hz, 1H), 3.52 (s, 3H), 1.34 (q, J = 3.7 Hz, 2H),0.75 (q, J = 3.7 Hz, 2H). Example 1-[5-cyclobutyl-2-(4- ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.16-9.07 (m, LC/MS GIII-31 methylpiperazin-1- 1H), 8.97(dd, J = 4.2, 1.7 Hz, 1H), 8.12-8.03 (m, 2H), (ESI+) yl)pyridin-3-yl]-N-7.95 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 8.3, 7.3 Hz, 1H), m/z 506(quinoline-5- 7.59 (dd, J = 8.7, 4.1 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H),(M + H)⁺. sulfonyl)cyclopropane- 3.47 (p, J = 8.7 Hz, 1H), 3.27-3.12 (m,4H), 2.79- 1-carboxamide 2.63 (m, 4H), 2.31 (ddt, J = 11.0, 8.3, 4.7 Hz,2H), 2.18- 1.95 (m, 3H), 1.94-1.80 (m, 1H), 1.34 (q, J = 3.2 Hz, 2H),0.86 (q, J = 3.5 Hz, 2H). Example 1-[5-cyclobutyl-2-(4- ¹H NMR (400 MHz,methanol-d₄) δ ppm 9.06 (d, J = LC/MS GIII-32 methylpiperazin-1- 8.8 Hz,1H), 8.20 (d, J = 7.3 Hz, 1H), 8.03 (d, J = 8.4 (ESI+)yl)pyridin-3-yl]-N-(2- Hz, 2H), 7.84 (d, J = 3.0 Hz, 1H), 7.72 (t, J =7.9 Hz, m/z 520 methylquinoline-5- 1H), 7.51-7.44 (m, 2H), 3.52-3.39 (m,1H), 3.10- (M + H)⁺. sulfonyl)cyclopropane- 2.93 (m, 4H), 2.74 (s, 3H),2.42-2.24 (m, 4H), 2.15- 1-carboxamide 1.95 (m, 3H), 1.91-1.83 (m, 1H),1.51 (q, J = 3.6 Hz, 2H), 0.96 (q, J = 3.8 Hz, 2H). Example1-[5-ethyl-2-(4- ¹H NMR (400 MHz, methanol-d₄) δ ppm 9.21 (ddd, J =LC/MS GIII-33 methylpiperazin-1- 8.7, 1.7, 0.9 Hz, 1H), 8.91 (dd, J =4.3, 1.7 Hz, 1H), (ESI+) yl)pyridin-3-yl]-N- 8.30 (dd, J = 7.3, 1.2 Hz,1H), 8.14 (dt, J = 8.5, 1.1 Hz, m/z 480 (quinoline-5- 1H), 7.89 (d, J =2.4 Hz, 1H), 7.80 (dd, J = 8.5, 7.3 Hz, (M + H)⁺. sulfonyl)cyclopropane-1H), 7.61 (dd, J = 8.7, 4.3 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1-carboxamide1H), 3.16-3.07 (s, 4H), 2.65-2.48 (m, 6H), 2.43 (s, 3H), 1.49 (q, J =3.7 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H), 0.98 (q, J = 3.8 Hz, 2H). Example1-(5-chloro-2- ¹H NMR (400 MHz, chloroform-d) δ ppm 8.97 (d, J = LC/MSGIII-34 fluoropyridin-3-yl)-N- 3.9 Hz, 1H), 8.79-8.64 (m, 1H), 8.34-8.16(m, 2H), (ESI+) (quinoline-5- 7.97 (d, J = 10.6 Hz, 1H), 7.70-7.57 (s,1H), 7.41- m/z 406 sulfonyl)cyclopropane- 7.31 (m, 2H), 1.48-1.43 (m,2H), 1.01-0.90 (m, 2H). and 408 1-carboxamide (M + H)⁺. Example 1-{5- ¹HNMR (400 MHz, methanol-d₄) δ ppm 9.06 (ddd, J = LC/MS GIII-35(hydroxymethyl)-2- 8.8, 1.6, 0.9 Hz, 1H), 8.98 (dd, J = 4.3, 1.6 Hz,1H), (ESI+) [(propan-2- 8.46 (dd, J = 7.5, 1.2 Hz, 1H), 8.33 (dt, J =8.5, 1.1 Hz, m/z 442 yl)oxy]pyridin-3-yl}- 1H), 8.03 (d, J = 2.3 Hz,1H), 7.92 (dd, J = 8.5, 7.5 Hz, (M + H)⁺. N-(quinoline-5- 1H), 7.65 (dd,J = 8.8, 4.2 Hz, 1H), 7.53 (d, J = 2.4 Hz, sulfonyl)cyclopropane- 1H),5.06 (hept, J = 6.1 Hz, 1H), 4.55 (s, 2H), 1.39- 1-carboxamide 1.34 (m,2H), 1.04 (d, J = 6.1 Hz, 6H), 1.03-0.98 (m, 2H). Example1-[5-cyclopropyl-2-(4- ¹H NMR (400 MHz, methanol-d₄) δ ppm 7.83 (d, J =LC/MS GIII-36 methylpiperazin-1- 2.4 Hz, 1H), 7.61 (dd, J = 7.4, 0.9 Hz,1H), 7.50 (dt, J = (ESI+) yl)pyridin-3-yl]-N- 8.1, 1.0 Hz, 1H), 7.32 (d,J = 3.1 Hz, 1H), 7.28 (d, J = m/z 480 (1H-indole-4- 2.4 Hz, 1H), 7.11(t, J = 7.8 Hz, 1H), 6.85 (dd, J = 3.1, (M + H)⁺. sulfonyl)cyclopropane-0.9 Hz, 1H), 4.83 (s, 6H), 3.08 (d, J= 6.5 Hz, 4H), 2.48 1-carboxamide(t, J = 4.9 Hz, 4H), 2.37 (s, 3H), 1.82 (tt, J = 8.4, 5.1 Hz, 1H), 1.55(q, J = 3.7 Hz, 2H), 0.98-0.85 (m, 4H), 0.68- 0.59 (m, 2H).

Biological Examples Determination of Biological Activity Cell SurfaceExpression-Horse Radish Peroxidase (CSE-HRP) Assay

A cellular assay for measuring the F508delCFTR cell surface expressionafter correction with test compounds either without or with aco-corrector (2 μM of3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoicacid), was developed in human lung derived epithelial cell line(CFBE41o-) (Veit G et al, (2012) Mol Biol Cell. 23(21): 4188-4202). Thedevelopment was achieved by expressing the F508delCFTR mutation alongwith a horseradish peroxidase (HRP) in the fourth exofacial loop, andthen measuring the HRP activity using luminescence readout from thesecells, CFBE41o-F508delCFTR-HRP, that were incubated overnight with thetest corrector compounds, either without or with the co-corrector. Forthis primary assay, the CFBE41o-F508delCFTR-HRP cells were plated in384-well plates (Greiner Bio-one; Cat 781080) at 4,000 cells/well alongwith 0.5 μg/mL doxycycline to induce the F508delCFTR-HRP expression andfurther incubated at 37° C., 5% CO₂ for 68-72 hours. The test compoundswere then added either without or with a co-corrector at the requiredconcentrations and further incubated for 18-24 hours at 33° C. Thehighest concentration tested was 20 μM or 30 μM (GI-1 to GIII-36) withan 8-point concentration response curve using a 3-fold dilution in boththe test compound without or with the co-corrector. Three replicateplates were run to determine one EC₅₀. All plates contained negativecontrols (dimethyl sulfoxide, DMSO) and positive control (2 μM or 3 μM(GI-1 to GIII-36) of3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoicacid) as well as on-plate concentration response of the positivecontrol. Post incubation, the plates were washed 5× times withDulbecco's phosphate buffered saline (DPBS), followed by the addition ofthe HRP substrate, luminol (50 μL), and measuring the HRP activity usingluminescence readout on EnVisionR Multilabel Plate Reader (Perkin Elmer;product number 2104-0010). The raw counts from the experiment wereanalyzed using AccelrysR Assay Explorer v3.3.

Z′ greater than 0.5 was used as passing quality control criteria for theplates.

The Z′ is defined as:

1−[3*SD_(positive Control)+3*SD_(Negative Control)/Absolute(Mean_(Postivie Control)−Mean_(Negative Control))]

wherein “SD” is standard deviation.

The % activity measured at each of the 8 test concentrations of the testcompound added either without or with a co-corrector (2 μM or 3 μM (GI-1to GIII-36) of3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoicacid) was normalized to the on-plate positive control using thefollowing formulae:

% activity (Test compound without co-corrector)=[(test compound withoutco-corrector response−DMSO response)/(positive control response−DMSOresponse)]*100

% activity (Test compound with co-corrector)=[(test compound withco-corrector response−DMSO response)/(positive control response−DMSOresponse)]*100

The maximum % activity achieved for the test compound either without orwith a co-corrector at any tested concentration is presented in Table 6along with the respective ECso's calculated using the following generalsigmoidal curve with variable Hill slope equation (described as Model 42in the Accelrys® Assay Explorer v3.3 software):

y=(a−d)/(1+(x/c){circumflex over ( )}b)+d

General sigmoidal curve with concentration, response, top, bottom, EC₅₀and Hill slope. This model describes a sigmoidal curve with anadjustable baseline, a. The equation can be used to fit curves whereresponse is either increasing or decreasing with respect to theindependent variable, “x”.

“x” is a concentration of drug under test.“y” is the response.“a” is the maximum response, and “d” is the minimum response“c” is the inflection point (EC₅₀) for the curve. That is, “y” ishalfway between the lower and upper asymptotes when x=c.“b” is the slope-factor or Hill coefficient. The sign ofb is positivewhen the response increases with increasing dose and is negative whenthe response decreases with increasing dose (inhibition).The data is presented with the qualifiers shown below:

TABLE 6 EC50 (μM) Without/with <3 +++ co-corrector ≥3 and <10 ++ ≥10 +Maximum % activity (%) Without <50 + co-corrector ≥50 and <150 ++ ≥150+++ With <150 + co-corrector ≥150 and <350 ++ ≥350 +++

Maximum % Maximum % EC50 activity EC50 activity (without (without (with(with Example co-corrector) co-corrector) co-corrector) co-corrector) #(μM) (%) (μM) (%) I-1 +++ +++ +++ +++ I-2 +++ +++ +++ +++ I-3 +++ ++++++ +++ I-4 +++ +++ +++ +++ I-5 ++ +++ +++ +++ I-6 +++ +++ +++ +++ I-7++ +++ +++ +++ I-8 +++ +++ +++ +++ I-9 +++ +++ +++ +++ I-10 ++ +++ ++++++ I-11 +++ +++ +++ +++ I-12 +++ +++ +++ +++ I-13 +++ +++ +++ +++ I-14+++ +++ +++ +++ I-15 ++ +++ ++ +++ I-16 ++ +++ +++ +++ I-17 +++ +++ ++++++ I-18 +++ +++ +++ +++ I-19 +++ +++ +++ +++ I-20 +++ +++ +++ +++ I-21+++ +++ +++ +++ I-22 ++ +++ +++ +++ I-23 ++ +++ +++ +++ I-24 +++ +++ ++++++ I-25 +++ +++ +++ +++ I-26 +++ +++ +++ +++ I-27 ++ +++ +++ +++ I-28+++ +++ +++ +++ I-29 +++ +++ +++ +++ I-30 +++ +++ +++ +++ I-31 +++ ++++++ +++ I-32 +++ +++ +++ +++ I-33 ++ +++ +++ +++ I-34 +++ +++ +++ +++I-35 +++ +++ +++ +++ I-36 +++ +++ +++ +++ I-37 +++ +++ +++ +++ I-38 ++++++ +++ +++ I-39 +++ +++ +++ +++ I-40 +++ +++ +++ +++ I-41 +++ +++ ++++++ I-42 +++ +++ +++ +++ I-43 +++ +++ +++ +++ I-44 +++ +++ +++ +++ I-45+++ +++ +++ +++ I-46 +++ +++ +++ +++ I-47 +++ +++ +++ +++ I-48 +++ ++++++ +++ I-49 +++ +++ +++ +++ I-50 +++ +++ +++ +++ I-51 +++ +++ +++ +++I-52 +++ +++ +++ +++ I-53 ++ +++ +++ +++ I-54 +++ +++ +++ +++ I-55 ++++++ +++ +++ I-56 +++ +++ +++ +++ I-57 +++ +++ +++ +++ I-58 ++ +++ ++++++ I-59 +++ +++ +++ +++ I-60 +++ +++ +++ +++ I-61 +++ +++ +++ +++ I-62+++ +++ +++ +++ I-63 +++ +++ +++ +++ I-64 +++ +++ +++ +++ I-65 ++ ++++++ +++ I-66 +++ +++ +++ +++ I-67 ++ +++ +++ +++ I-68 +++ +++ +++ +++I-69 +++ +++ +++ +++ I-70 +++ +++ +++ +++ I-71 +++ +++ +++ +++ I-72 +++++ +++ +++ I-73 +++ +++ +++ +++ I-74 +++ +++ +++ +++ I-75 ++ +++ ++++++ I-76 ++ +++ +++ +++ I-77 +++ +++ +++ +++ I-78 +++ +++ +++ +++ I-79+++ +++ +++ +++ I-80 ++ +++ +++ +++ I-81 +++ +++ +++ +++ I-82 +++ ++++++ +++ I-83 +++ +++ +++ +++ I-84 +++ +++ +++ +++ I-85 + + ++ ++ I-86+++ +++ +++ +++ I-87 +++ +++ +++ +++ I-88 ++ +++ +++ +++ I-89 +++ ++++++ +++ I-90 ++ ++ ++ +++ I-91 +++ +++ +++ +++ I-92 +++ +++ +++ +++ I-93++ +++ +++ +++ I-94 +++ +++ +++ +++ I-95 +++ +++ +++ +++ I-96 +++ ++++++ +++ I-97 +++ +++ +++ +++ I-98 +++ +++ +++ +++ I-99 +++ +++ +++ +++I-100 +++ +++ +++ +++ I-101 +++ +++ +++ +++ I-102 +++ +++ +++ +++ I-103+++ +++ +++ +++ I-104 +++ +++ +++ +++ I-105 +++ +++ +++ +++ I-106 ++ ++++++ +++ I-107 +++ +++ +++ +++ I-108 +++ +++ +++ +++ I-109 +++ +++ ++++++ I-110 +++ +++ +++ +++ I-111 +++ +++ +++ +++ I-112 +++ +++ +++ +++I-113 +++ +++ +++ +++ I-114 +++ +++ +++ +++ I-115 +++ +++ +++ +++ I-116+++ +++ +++ +++ I-117 +++ +++ +++ +++ I-118 +++ +++ +++ +++ I-119 ++++++ +++ +++ I-122 +++ +++ +++ +++ I-123 +++ +++ +++ +++ I-124 +++ ++++++ +++ II-1 ++ +++ ++ +++ II-2 ++ +++ ++ +++ II-3 ++ +++ +++ +++ II-4++ ++ ++ +++ II-5 ++ + ++ ++ II-6 ++ +++ +++ +++ II-7 ++ +++ +++ +++II-8 ++ +++ +++ +++ II-9 ++ +++ +++ +++ II-10 ++ +++ ++ +++ II-11 ++ ++++++ +++ II-12 ++ +++ +++ +++ II-13 +++ +++ +++ +++ II-14 +++ +++ +++ +++II-15 ++ +++ +++ +++ II-16 ++ +++ +++ +++ II-17 +++ +++ +++ +++ II-18 +++++ +++ +++ II-19 ++ ++ ++ +++ II-20 ++ +++ +++ +++ II-21 +++ +++ ++++++ II-22 ++ +++ +++ +++ II-23 ++ ++ ++ +++ II-24 +++ +++ +++ +++ II-25++ +++ +++ +++ II-26 +++ +++ +++ +++ II-27 +++ +++ +++ +++ II-28 +++ ++++++ +++ II-29 +++ +++ +++ +++ II-30 ++ +++ +++ +++ II-31 ++ +++ +++ +++II-32 ++ +++ +++ +++ II-33 ++ +++ +++ +++ II-35 ++ +++ +++ +++ II-36 ++++++ +++ +++ II-37 +++ +++ +++ +++ II-38 ++ +++ +++ +++ II-39 +++ ++ ++++++ II-40 ++ +++ ++ +++ II-41 ++ ++ +++ +++ II-42 ++ ++ +++ +++ II-43+++ ++ +++ +++ II-44 +++ +++ +++ +++ II-45 ++ +++ +++ +++ II-46 +++ ++++++ +++ II-47 +++ +++ +++ +++ II-48 + + ++ ++ II-49 +++ +++ +++ +++II-50 ++ +++ +++ +++ II-51 +++ +++ +++ +++ II-52 +++ +++ +++ +++ II-53++ +++ +++ +++ II-54 +++ +++ +++ +++ II-55 +++ +++ +++ +++ II-56 ++ +++++ +++ II-57 +++ +++ +++ +++ II-58 +++ +++ +++ +++ II-59 +++ +++ +++ +++II-60 +++ +++ +++ +++ II-61 +++ +++ +++ +++ II-62 +++ +++ +++ +++ II-63+++ +++ +++ +++ II-64 ++ +++ +++ +++ II-65 +++ +++ +++ +++ II-66 +++ ++++++ +++ II-67 +++ +++ +++ +++ II-68 ++ +++ +++ +++ II-69 +++ +++ +++ +++II-70 +++ +++ +++ +++ II-71 +++ +++ +++ +++ II-72 +++ +++ +++ +++ II-73+++ +++ +++ +++ II-74 +++ +++ +++ +++ II-75 +++ +++ +++ +++ II-76 ++ +++++ +++ II-77 +++ +++ +++ +++ II-78 +++ +++ +++ +++ II-79 +++ +++ +++ +++II-80 ++ +++ +++ +++ II-81 +++ +++ +++ +++ II-82 ++ +++ +++ +++ II-83+++ +++ +++ +++ II-84 +++ +++ +++ +++ II-85 +++ +++ +++ +++ II-86 ++ ++++++ +++ II-87 ++ +++ +++ +++ II-88 ++ +++ +++ +++ II-89 ++ +++ ++ +++II-90 ++ +++ ++ +++ II-91 ++ +++ +++ +++ II-92 +++ +++ +++ +++ II-93 ++++++ +++ +++ II-94 +++ +++ +++ +++ II-95 +++ +++ +++ +++ II-96 +++ ++++++ +++ II-97 +++ +++ +++ +++ II-98 +++ +++ +++ +++ II-99 +++ +++ ++++++ II-100 ++ +++ +++ +++ II-101 +++ +++ +++ +++ II-102 ++ +++ +++ +++II-103 +++ +++ +++ +++ II-104 +++ +++ +++ +++ II-105 +++ +++ +++ +++II-106 ++ +++ ++ +++ II-107 +++ +++ +++ +++ II-108 ++ +++ ++ +++ II-109++ +++ ++ +++ II-110 +++ +++ +++ +++ II-111 +++ +++ +++ +++ II-112 ++++++ +++ +++ II-113 +++ +++ +++ +++ II-115 +++ +++ +++ +++ II-117 ++ ++++++ +++ III-3 ++ ++ ++ +++ III-5 + + + + III-6 + + ++ ++ III-7 + + ++ ++III-8 + + ++ ++ III-9 + + ++ + III-10 + + + + III-11 + + + + III-12 + +++ ++ III-13 ++ + +++ ++ III-14 + + + + III-15 ++ + ++ ++ III-16 + + + +III-17 + + + + III-19 + + + + III-20 + + + + III-22 + + ++ ++ III-23 ++++ ++ +++ III-24 + + + ++ III-25 + + ++ + III-26 ++ + ++ ++III-27 + + + + III-28 + + ++ + III-29 ++ + ++ ++ III-30 + + ++ ++III-31 + + ++ ++ III-32 ++ + ++ ++ III-33 ++ + ++ ++ III-34 + + + ++III-35 + + + ++ III-36 + + + + III-37 + + ++ ++ III-55 + + + +III-56 + + + + III-57 + + + + III-58 + + ++ ++ III-59 + + ++ +III-61 + + ++ ++ III-62 + + + + III-63 + + ++ ++ III-64 + + + +III-66 + + ++ ++ III-67 + + + + III-68 + + +++ + III-70 + + + + III-71++ ++ ++ +++ III-72 + + + + III-73 + + + + III-74 + + + + III-75 + + + +III-76 + + + + III-77 + + + + III-78 + + + + III-79 + + ++ +III-80 + + + + III-81 + + + + III-82 + + + + III-83 + + + ++III-84 + + + + III-85 ++ ++ ++ +++ III-86 ++ + ++ ++ III-87 ++ ++ ++ +++III-88 ++ + ++ ++ III-89 ++ + +++ ++ III-90 + + + + III-91 + +++ ++ +++III-92 ++ +++ ++ +++ III-93 ++ +++ ++ +++ III-94 + + + + III-95 ++ +++++ +++ III-96 ++ ++ ++ +++ III-97 ++ +++ ++ +++ III-98 ++ +++ ++ +++III-99 ++ ++ ++ +++ III-100 ++ +++ ++ +++ III-101 +++ +++ +++ +++III-102 ++ +++ ++ +++ III-103 ++ +++ +++ +++ III-104 + + ++ ++III-105 + + + + III-106 + + + + III-107 + + + + III-108 + + ++ ++III-109 + + + + III-111 + + ++ ++ III-112 + + + + III-113 + + ++ ++III-114 + + ++ + III-115 + + + + III-116 + + + + III-119 + + + +III-120 + + + + III-121 + + + + III-122 ++ +++ ++ +++ III-123 ++ +++ ++++++ III-124 ++ ++ ++ +++ III-125 ++ +++ ++ +++ III-126 +++ ++ +++ ++III-127 ++ +++ +++ +++ III-128 ++ + ++ ++ III-129 ++ +++ ++ +++ III-130++ +++ +++ +++ III-131 ++ +++ ++ +++ III-132 +++ +++ +++ +++ III-133 ++++++ +++ +++ III-134 +++ +++ +++ +++ GI-1 +++ +++ +++ +++ GI-2 +++ ++++++ +++ GI-3 +++ +++ +++ +++ GI-4 ++ +++ +++ +++ GI-5 ++ +++ +++ +++GI-6 ++ +++ +++ +++ GI-7 ++ +++ +++ +++ GI-8 +++ +++ +++ +++ GI-9 ++++++ +++ +++ GI-10 +++ +++ +++ +++ GI-11 +++ +++ +++ +++ GI-12 +++ ++++++ +++ GI-13 +++ +++ +++ +++ GI-14 ++ +++ +++ +++ GI-15 +++ +++ +++ +++GI-16 ++ +++ +++ +++ GI-17 ++ +++ +++ +++ GI-18 ++ +++ +++ +++ GI-19 +++++ +++ +++ GI-20 +++ +++ +++ +++ GI-21 +++ +++ +++ +++ GI-22 +++ ++++++ +++ GI-23 +++ +++ +++ +++ GI-24 +++ +++ +++ +++ GI-25 ++ +++ +++ +++GI-26 ++ +++ +++ +++ GI-27 ++ +++ +++ +++ GI-28 ++ +++ +++ +++ GI-29 ++++++ +++ +++ GI-30 +++ +++ +++ +++ GI-31 +++ +++ +++ +++ GI-32 ++ +++ ++++++ GI-33 ++ +++ +++ +++ GI-34 ++ +++ +++ +++ GI-35 ++ +++ +++ +++ GI-36++ +++ +++ +++ GI-37 ++ +++ +++ +++ GI-38 +++ +++ +++ +++ GI-39 +++ ++++++ +++ GI-40 +++ +++ +++ +++ GI-41 +++ +++ +++ +++ GI-42 +++ +++ ++++++ GI-43 +++ +++ +++ +++ GI-44 +++ +++ +++ +++ GI-45 +++ +++ +++ +++GI-46 +++ +++ +++ +++ GI-47 +++ +++ +++ +++ GI-48 +++ +++ +++ +++ GI-49+++ +++ +++ +++ GI-50 +++ +++ +++ +++ GI-51 +++ +++ +++ +++ GI-52 ++++++ +++ +++ GI-53 +++ +++ +++ +++ GI-54 ++ +++ ++ +++ GI-55 ++ +++ ++++++ GI-56 ++ +++ +++ +++ GI-57 +++ +++ +++ +++ GI-58 +++ +++ +++ +++GI-59 ++ +++ +++ +++ GI-60 +++ +++ +++ +++ GI-61 +++ +++ +++ +++ GI-62+++ +++ +++ +++ GI-63 +++ +++ +++ +++ GI-64 +++ +++ +++ +++ GI-65 ++++++ +++ +++ GI-66 +++ +++ +++ +++ GI-67 ++ +++ +++ +++ GI-68 +++ +++ ++++++ GI-69 +++ +++ +++ +++ GI-70 +++ +++ +++ +++ GI-71 ++ +++ +++ +++GI-72 +++ +++ +++ +++ GI-73 ++ +++ +++ +++ GI-74 ++ +++ +++ +++ GI-75 +++++ +++ +++ GI-76 +++ +++ +++ +++ GI-77 +++ +++ +++ +++ GI-78 +++ ++++++ +++ GI-79 +++ +++ +++ +++ GI-80 +++ +++ +++ +++ GI-81 +++ +++ ++++++ GI-82 +++ +++ +++ +++ GI-83 ++ +++ +++ +++ GI-84 ++ +++ +++ +++GI-85 ++ +++ +++ +++ GI-86 +++ +++ +++ +++ GI-87 ++ +++ +++ +++ GI-88+++ +++ +++ +++ GI-89 +++ +++ +++ +++ GI-90 +++ +++ +++ +++ GI-91 ++ ++++++ +++ GI-92 +++ +++ +++ +++ GI-93 +++ +++ +++ +++ GI-94 +++ +++ ++++++ GI-95 +++ +++ +++ +++ GI-96 ++ +++ +++ +++ GI-97 +++ +++ +++ +++GI-98 +++ +++ +++ +++ GI-99 +++ +++ +++ +++ GI-100 +++ +++ +++ +++GI-101 ++ +++ +++ +++ GI-102 ++ +++ +++ +++ GI-104 +++ +++ +++ +++GI-105 +++ +++ +++ +++ GI-106 +++ +++ +++ +++ GI-107 +++ +++ +++ +++GI-1O8 +++ +++ +++ +++ GI-109 ++ +++ +++ +++ GI-110 +++ +++ +++ +++GI-111 +++ +++ +++ +++ GI-112 ++ +++ +++ +++ GI-113 +++ +++ +++ +++GI-114 ++ +++ +++ +++ GI-115 +++ +++ +++ +++ GI-116 ++ +++ +++ +++GI-117 +++ +++ +++ +++ GI-118 +++ +++ +++ +++ GI-119 +++ +++ +++ +++GI-120 ++ +++ +++ +++ GI-121 +++ +++ +++ +++ GII-1  ++^(a) +  ++^(a) ++GII-2 ++ ++ ++ ++ GII-3 ++ ++ ++ ++ GII-4 ++ ++ ++ ++ GII-5 ++ ++ ++ ++GII-6 ++ ++ ++ ++ GII-7 ++ ++ ++ +++ GII-8 + +  ++^(a) ++ GII-9 ++ ++ ++++ GII-10 ++ +++ ++ +++ GII-11  ++^(a) ++ ++ +++ GII-12 ++ ++ ++ +++GII-13 ++ ++ ++ +++ GII-14 ++ +++ ++ +++ GII-15 ++ +++ ++ +++ GII-16 ++^(a) ++ ++ ++ GII-17 ++ + ++ ++ GII-18 ++ +++ ++ +++ GII-19  ++^(a)++ ++ +++ GII-20  ++^(a) ++  ++^(a) ++ GII-21 + + ++ ++ GII-22 ++ +++ +++++ GII-23  ++^(a) ++  ++^(a) ++ GII-24  ++^(a) ++ ++ ++ GII-25 ++ +++++ +++ GII-26 ++ +++ ++ +++ GII-27 ++ ++ ++ ++ GII-28  ++^(a) ++ ++ ++GII-29 ++ +++ ++ +++ GII-30 ++ +++ ++ +++ GII-31 ++ +++ ++ +++ GII-32 ++^(a) ++  ++^(a) ++ GII-33  ++^(a) ++  ++^(a) ++ GII-34  ++^(a) ++ ++^(a) ++ GII-35 ++ +++ ++ ++ GII-36 ++ ++ ++ +++ GII-37 ++ +++ ++ +++GII-38 ++ +++ ++ +++ GII-39 ++ ++ ++ ++ GII-40 ++ +++ ++ +++ GII-41 ++++ ++ +++ GII-42  ++^(a) ++ ++ ++ GII-43  ++^(a) ++ ++ ++ GII-44  ++^(a)++  ++^(a) ++ GII-45 ++ +++ ++ +++ GII-46  ++^(a) ++ ++ ++ GII-47 +++++ + +++ GII-48 ++ +++ ++ +++ GII-49 ++ +++ ++ +++ GII-50  ++^(a) +++++ +++ GII-51  ++^(a) ++ ++ ++ GII-52 ++ ++ ++ ++ GII-53 ++ +++ ++ +++GII-54 ++ +++ ++ +++ GII-55 ++ +++ ++ +++ GII-56 ++ +++ ++ +++ GII-57 +++++ ++ +++ GII-58 ++ +++ ++ +++ GII-59 ++ +++ ++ +++ GIII-1  ++^(a) + ++^(a) ++ GIII-2 + + + + GIII-3 ++ +++ ++ +++ GIII-5  ++^(a) +  ++^(a)++ GIII-6 + + + + GIII-7  ++^(a) +  ++^(a) ++ GIII-8  ++^(a) ++  ++^(a)++ GIII-10  ++^(a) ++  ++^(a) ++ GIII-11  ++^(a) ++  ++^(a) ++GIII-12 + + + + GIII-13 + +  ++^(a) ++ GIII-14 ++ +++ ++ +++ GIII-15 ++^(a) +  ++^(a) ++ GIII-16 + + + + GIII-17  ++^(a) ++  ++^(a) ++GIII-18  ++^(a) ++  ++^(a) ++ GIII-19  ++^(a) ++  ++^(a) ++ GIII-20 ++^(a) ++  ++^(a) ++ GIII-21  ++^(a) ++  ++^(a) ++ GIII-22  ++^(a) ++ ++^(a) ++ GIII-23 + ++ + ++ GIII-24 + + + + GIII-25 ++^(a) ++  ++^(a)++ GIII-26 + + + ++ GIII-28 + + + ++ GIII-29 + + + + GIII-30 + + ++^(a) + GIII-31 + + + + GIII-32 + + + + GIII-33 + + + +GIII-34 + + + + GIII-35 + + + + GIII-36 + + + + ++^(a) = data wasreported as >3.00 μM

The data provided in the present application demonstrate that thecompounds of the invention demonstrate activity in vitro, and may beuseful in vivo in the treatment of cystic fibrosis.

Further benefits of Applicants' invention will be apparent to oneskilled in the art from reading this patent application.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the embodiments will be apparent to those skilled inthe art. Such changes and modifications, including without limitationthose relating to the chemical structures, substituents, derivatives,intermediates, syntheses, formulations, or methods, or any combinationof such changes and modifications of use of the invention, may be madewithout departing from the spirit and scope thereof.

We claim:
 1. A compound or pharmaceutically acceptable salt thereof,selected from the group consisting of:1-(5-bromo-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyclobutyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyclobutyl-2-methoxypyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(2,6-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;1-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;1-(5-bromo-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyclopropyl-2-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(2-methoxy-5-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyclobutyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyclopropyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;1-(2,5-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(2,5-dimethoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-(dimethylamino)-5-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(5-tert-butyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(2,6-dimethoxy-3-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyclobutyl-2-methoxyphenyl)-N-(2,3-dihydro-H-indole-4-sulfonyl)cyclopropane-1-carboxamide;1-(2-methoxyquinolin-3-yl)-N-(2-methylquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(2-methoxyquinolin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(3-methoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(3-methoxy-4-methylphenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;N-(quinoline-5-sulfonyl)-1-[2-(trifluoromethoxy)phenyl]cyclobutane-1-carboxamide;1-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(1-ethyl-5-methyl-1H-pyrazol-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(2-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclobutane-1-carboxamide;1-(2-methoxy-5-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;1-(5-cyclopentyl-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;1-[5-(butan-2-yl)-2-methoxyphenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclobutane-1-carboxamide;1-[2-chloro-5-(trifluoromethoxy)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-methoxy-5-(trifluoromethyl)phenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;methyl4-methoxy-3-{1-[(naphthalene-1-sulfonyl)carbamoyl]cyclopropyl}benzoate;1-(5-bromo-2-methoxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;1-(6-methoxy-2,3-dimethylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(3-cyclopropyl-6-methoxy-2-methylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyclobutyl-2-methoxy-4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyclobutyl-2-methoxyphenyl)-N-(1-methyl-2,3-dihydro-1H-indole-4-sulfonyl)cyclopropane-1-carboxamide;1-(2-methoxy-6-methylphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(3-methoxyphenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;N-(benzenesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;N-(3-cyanobenzene-1-sulfonyl)-4-(3-fluorophenyl)oxane-4-carboxamide;N-(benzenesulfonyl)-1-(4-methoxyphenyl)cyclopropane-1-carboxamide;N-(benzenesulfonyl)-1-(4-chlorophenyl)cyclobutane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(2,3-dihydro-1H-indene-5-sulfonyl)cyclopropane-1-carboxamide;N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;N-(4-chlorobenzene-1-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide;methyl5-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}-4-methoxythiophene-3-carboxylate;1-(2,4-dichlorophenyl)-N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-[2-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-[4-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-[3-(trifluoromethyl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-[4-(2-oxopyrrolidin-1-yl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-[5-(1,2-oxazol-5-yl)thiophene-2-sulfonyl]cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-[4-(pyrrolidine-1-sulfonyl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;N-(4-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)-N-methylcyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-{4-[(propan-2-yl)oxy]benzene-1-sulfonyl}cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-[6-(morpholin-4-yl)pyridine-3-sulfonyl]cyclopropane-1-carboxamide;benzyl4-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;N-(2-chlorobenzene-1-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(4-methoxybenzene-1-sulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(3,4-dimethoxybenzene-1-sulfonyl)cyclopropane-1-carboxamide;N-(3-chlorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(naphthalene-2-sulfonyl)cyclopropane-1-carboxamide;N-(cyclopropanesulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;N-(benzenesulfonyl)-1-(4-methylphenyl)cyclopropane-1-carboxamide;N-(benzenesulfonyl)-1-(2-fluorophenyl)cyclopropane-1-carboxamide;N-(benzenesulfonyl)-1-(4-fluorophenyl)cyclopropane-1-carboxamide;N-(benzenesulfonyl)-1-(2-chlorophenyl)cyclopropane-1-carboxamide;N-(benzenesulfonyl)-1-(4-chlorophenyl)cyclopropane-1-carboxamide;N-(benzenesulfonyl)-1-(3,4-dichlorophenyl)cyclopropane-1-carboxamide;1-(2-fluorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(1,1-dioxo-1λ⁶-thiolane-3-sulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(4-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;N-(2-cyano-5-fluorobenzene-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;N-(2-chloro-5-nitrobenzene-1-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide;1-(3-chlorophenyl)-N-(6-ethoxy-1,3-benzothiazole-2-sulfonyl)cyclopropane-1-carboxamide;1-(3-chlorophenyl)-N-(5-hydroxynaphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(3-chlorophenyl)-N-[5-(dimethylamino)naphthalene-1-sulfonyl]cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(pyridine-3-sulfonyl)cyclopropane-1-carboxamide;N-(6-chloropyridine-3-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;N-(benzenesulfonyl)-2,2-dimethyl-1-phenylcyclopropane-1-carboxamide;methyl5-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}furan-2-carboxylate;N-(5-bromothiophene-2-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-[3-(trifluoromethoxy)benzene-1-sulfonyl]cyclopropane-1-carboxamide;methyl2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoate;methyl4-chloro-2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoate;2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoicacid;4-chloro-2-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}benzoicacid; benzyl4-{[1-(4-methylphenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;benzyl4-{[1-(3,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;N-(benzenesulfonyl)-1-(3-bromophenyl)cyclopropane-1-carboxamide;1-(3-chlorophenyl)-N-[2-(trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl]cyclopropane-1-carboxamide;1-(3-chlorophenyl)-N-[4-(1H-pyrazol-1-yl)benzene-1-sulfonyl]cyclopropane-1-carboxamide;1-(3-chlorophenyl)-N-(3,4-dimethylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;1-(3-chlorophenyl)-N-(2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)cyclopropane-1-carboxamide;N-(1-acetyl-2,3-dihydro-1H-indole-5-sulfonyl)-1-(3-chlorophenyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(piperidine-4-sulfonyl)cyclopropane-1-carboxamide;N-(1-acetylpiperidine-4-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-[1-(3-phenylpropanoyl)piperidine-4-sulfonyl]cyclopropane-1-carboxamide;tert-butyl4-{[1-(2,4-dichlorophenyl)cyclopropane-1-carbonyl]sulfamoyl}piperidine-1-carboxylate;4-(3-methoxyphenyl)-N-(2-methylbenzene-1-sulfonyl)oxane-4-carboxamide;N-(2-methylbenzene-1-sulfonyl)-4-(3-methylphenyl)oxane-4-carboxamide;1-(3-chlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopentane-1-carboxamide;1-(3-chlorophenyl)-N-(5-methylpyridine-2-sulfonyl)cyclopropane-1-carboxamide;1-(2-methoxyphenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;1-(2H-1,3-benzodioxol-5-yl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;1-(4-chlorophenyl)-N-(2-methylbenzene-1-sulfonyl)cyclopropane-1-carboxamide;tert-butyl4-(4-fluorophenyl)-4-[(naphthalene-1-sulfonyl)carbamoyl]piperidine-1-carboxylate;1-(3,4-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclopentane-1-carboxamide;1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(3-bromophenyl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(3-bromophenyl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(5-cyano-2-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[5-(bicyclo[1.1.1]pentan-1-yl)-2-methoxyphenyl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(trifluoromethanesulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(2,2,2-trifluoroethanesulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(propane-1-sulfonyl)cyclopropane-1-carboxamide;N-(3-chloropropane-1-sulfonyl)-1-(2,4-dichlorophenyl)cyclopropane-1-carboxamide;1-(3-chlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;1-(2,4-dichlorophenyl)-N-(propane-2-sulfonyl)cyclopropane-1-carboxamide;1-(4-methylphenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;1-(4-fluorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;1-(2-chlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;1-(4-chlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;1-(3,4-dichlorophenyl)-N-(phenylmethanesulfonyl)cyclopropane-1-carboxamide;N-(pentane-3-sulfonyl)-1-phenylcyclopropane-1-carboxamide;4-(3-methoxyphenyl)-N-(propane-1-sulfonyl)oxane-4-carboxamide;4-(3-methylphenyl)-N-(propane-1-sulfonyl)oxane-4-carboxamide;1-(3,4-dimethoxyphenyl)-N-(naphthalene-1-sulfonyl)cyclobutane-1-carboxamide;1-(3-methoxy-6-methylpyridin-2-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-{5-bromo-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(5-chloro-2-methoxypyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-[2-cyclopropyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-propyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-(propan-2-yl)-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-cyclobutyl-6-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-{5-ethyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[5-cyclobutyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-{5-[1-(methoxymethyl)cyclopropyl]-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(2,4-dimethoxypyrimidin-5-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;N-(naphthalene-1-sulfonyl)-1-{2-[(propan-2-yl)oxy]pyridin-3-yl}cyclopropane-1-carboxamide;1-{2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-{2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,34-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[5-chloro-2-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(5-chloro-2-methoxypyridin-4-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-methoxy-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(6-methoxy-2-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(4-ethylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-(4-ethylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(6-methoxy-4-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;1-{6-methoxy-4-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-{5-cyclobutyl-2-[(propan-2-yl)oxy]pyridin-3-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-{2-cyclobutyl-5-[(propan-2-yl)oxy]pyridin-4-yl}-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[5-cyclopropyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;N-(2-methylquinoline-5-sulfonyl)-1-[2-(pyrrolidin-1-yl)pyridin-3-yl]cyclopropane-1-carboxamide;1-[5-ethyl-2-(pyrrolidin-1-yl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(4-ethylpyridin-3-yl)-N-(quinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(2-fluoro-5-methylpyridin-4-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(2,4-dimethoxypyrimidin-5-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(6-methoxy-2-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-(6-methoxy-4-methylpyridin-3-yl)-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide;1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(naphthalene-1-sulfonyl)cyclopropane-1-carboxamide;and1-[2-chloro-6-(trifluoromethyl)pyridin-3-yl]-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)cyclopropane-1-carboxamide.